Amido heteroaromatic compounds

ABSTRACT

The specification relates to compounds of Formula (I):and to pharmaceutically acceptable salts thereof, to processes and intermediates used for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of diseases such as liver disease.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This specification claims the benefit of priority to U.S. ProvisionalPatent Applications No. 63/364,976 (filed 19 May 2022), 63/367,843(filed 7 Jul. 2022) and 63/383,982 (filed 16 Nov. 2022). The entire textof the above-referenced patent applications is incorporated by referenceinto this specification.

This specification relates to certain amido heteroaromatic compounds andpharmaceutically acceptable salts thereof that inhibit 17β hydroxysteroid dehydrogenase 13 (17βHSD13 or HSD17B13), and their use intreating diseases such as liver disease. This specification also relatesto processes and intermediate compounds involved in the preparation ofthe amido heteroaromatic compounds and to pharmaceutical compositionscontaining them.

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of liverdisease ranging from simple steatosis (non-alcoholic fatty liver), tonon-alcoholic steatohepatitis (NASH) with or without fibrosis, tocirrhosis. Hepatic steatosis is defined as excess fat accumulation inthe liver with greater than 5% induced by causes other than alcoholintake. NASH is defined by hepatic steatosis with inflammation andhepatocyte injury, with or without fibrosis. It is estimated thatapproximately 25% of the global population has NAFLD, and mortality dueto NAFLD-related disease is expected to increase significantly through2030.

To date, there are no approved treatments for NAFLD (such as NASH) andtherapeutic interventions focus on addressing co-morbidities thatcontribute to the pathogenesis of NAFLD, including treating insulinresistance, obesity, type II diabetes mellitus, and dyslipidemia.

Recently, a variant in the 17βHSD13 gene, was associated in an alleledose-dependent manner with decreased serum aminotransferases levels, aswell as a lower risk of liver disease, including alcoholic andnon-alcoholic liver disease, cirrhosis and hepatocellular carcinoma(HCC) (Abul-Husn et al, N Engl J Med. 2018, 378(12), 1096-106, Wang etal, Eur Rev Med Pharmacol Sci, 2020, 24(17), 8997-9007). The 17βHSD13splice variant (rs72613567:TA) results in a truncated, unstable andenzymatically inactive protein and has thus been characterized as an17βHSD13 Loss of Function (LoF) variant (Ma et al, Hepatology 2019,69(4), 1504-19). The association between the LoF 17βHSD13(rs72613567:TA) and decreased disease severity has been replicated inadditional cohorts with histologically proven NAFLD and was alsoassociated with lower plasma transaminases, reduced risk of cirrhosis,HCC and liver related mortality in a study of 111612 individuals fromthe Danish general population (Gellert-Kristensen et al, Hepatology,2020, 71(1), 56-66). Interestingly, the protective effect of the LoF17βHSD13 (rs72613567:TA) variant on plasma transaminases levels appearsto be amplified by several key risk factors of liver disease such asobesity, alcohol consumption, as well as established genetic riskfactors such as, but not limited to, the (rs738409 C>G) variant inpatatin-like phospholipase domain-containing protein 3 (PNPLA3).Further, two additional 17βHSD13LoF variants (rs62305723) and(rs143404524) were also reported to confer protection from chronic liverdisease progression (Kozlitina et al, N Engl J Med, 2018, 379(19),1876-7). In general, the LoF 17βHSD13 protective variants has a strongerassociation with fibrosis and progression to advance liver disease butis not associated with steatosis.

Based on the genetic validation of 17βHSD13LoF variants conferringprotection against liver disease risk and progression, inhibition of17βHSD13 activity with small molecules inhibitors could be an effectivetherapeutic approach for treating liver diseases such as NAFLD (forexample NASH, liver fibrosis, cirrhosis and isolated steatosis), liverinflammation, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV)and hepatocellular carcinoma (HCC), such as in individuals harbouringseveral key risk factors of liver disease such as obesity, alcoholconsumption, as well as established genetic risk factors such as the(rs738409 C>G) variant in PNPLA3.

The compounds of the disclosure provide an anti-liver disease effect by,as a minimum, acting as 17βHSD13 inhibitors. Further, compounds of thedisclosure may selectively inhibit 17βHSD13 over 17βHSD4 and/or 17βHSD9.

Fifteen 17βHSD (HSD17B) members have been identified in human. Thesequence homology among the different members is rather low, but theoverall structure seems conserved. 17β-Hydroxysteroid dehydrogenases aremainly involved in sex hormone metabolism. Some 17βHSD enzymes also playkey roles in cholesterol and fatty acid metabolism (Labrie et al.Journal of Molecular Endocrinology, 2000, 25, 1-16, Wen Su et al.Molecular and Cellular Endocrinology, 2019, 489, 119-125). A cleanoff-target profile is an advantage for a 17βHSD13 inhibitor to avoidpotential toxicity caused by off-target activity. This includesselectivity to other 17βHSD members.

17βHSD4/D-bifunctional protein (DBP) is involved in fatty acidO-oxidation and steroid metabolism. 17βHSD4 is ubiquitously expressedand play an important role in the inactivation of estrogens in a largeseries of peripheral tissues. Mutations in 17βHSD4 are known to causeDBP deficiency, an autosomal-recessive disorder of peroxisomal fattyacid O-oxidation that is generally fatal within the first two years oflife. A homozygous missense variant in 17βHSD4 has been identified inPerrault syndrome, a recessive disorder characterized by ovariandysgenesis in females, sensorineural deafness in both males and females,and in some patients, neurological manifestations (Pierce et al. Am. J.Hum. Genet., 2010, 87, 282-8; and Chen et al. BMC Med Genet., 2017, 18,91).

17βHSD9/RDH5 (retinol dehydrogenase 5) is involved in retinoidmetabolism. The enzyme is mainly expressed in the retinal pigmentepithelium. The RDH5 gene encodes the enzyme that is a part of thevisual cycle, the 11-cis retinol dehydrogenase, catalysing the reductionof 11-cis-retinol to 11-cis-retinal. RDH5 gene mutations cause aprogressive cone dystrophy or macular dystrophy as well as nightblindness. Fundus albipunctatus is a rare, congenital form of nightblindness with rod system impairment, characterised by the presence ofnumerous small, white-yellow retinal lesions. This disorder is causedmostly by mutations in the RDH5 gene (Hotta et al. Am. J. Ophthalmol.,2003, 135, 917-9; and Skorczyk-Werner et al. J. Appl. Genet., 2015, 56,317-27).

The compounds of the specification may also exhibit advantageousphysical properties (for example, lower lipophilicity, higher aqueoussolubility, higher permeability, lower plasma protein binding, and/orgreater chemical stability), and/or favourable toxicity profiles (forexample a decreased activity at hERG), and/or favourable metabolic orpharmacokinetic profiles, in comparison with other known 17βHSD13inhibitors. Such compounds may therefore be especially suitable astherapeutic agents, such as for the treatment of liver disease.

GENERAL DESCRIPTION

According to one aspect of the specification there is provided acompound of Formula (I);

wherein,A is selected from

each R^(A) is independently selected from H, halo, R^(X), —OR^(x), and—CN, wherein each R^(X) is independently C₁₋₃ alkyl optionallysubstituted with one to three F;R^(B) is halo, —CHF₂, —CF₃, —OCHF₂ or —OCF₃;one of X¹, X² and X³ is selected from NH, O and S and the other two ofX¹, X² and X³ are independently selected from N and CR^(Y), wherein eachR^(Y) is independently H, —CN, —C(═O)N(R⁷)₂ or R^(XA), wherein R^(XA) isindependently C₁₋₃ alkyl optionally substituted with one to three F;R¹ and R² are such that;(i) R¹ and R², taken together with the N atom to which they areattached, form a ring system, wherein the ring system is optionallysubstituted with one or more R^(C), wherein each R^(C) is independentlyselected from F, R³, R⁴, —O(R⁴), —O(R⁵), R⁵, R⁶, —OH, —CN, oxo and—C(═O)N(R^(7A))₂;(ii) R¹ is selected from R⁸ and R^(4A), and R² is selected from R^(8A)and H; or(iii) R¹ is R^(5A) and R² is R^(8B);each R³ is independently C₁₋₄ alkyl or C₃₋₆ cycloalkyl, each of whichare optionally substituted with one or more groups independentlyselected from R^(4X), R^(5x), —O(R^(4X)), —O(R^(5X)) and F;each R^(3X) is independently C₁₋₄ alkyl or C₃₋₆ cycloalkyl, each ofwhich are optionally substituted with one or more F;each R⁴ and R^(4B) are independently monocyclic or bicyclic 5 to 9membered heteroaryl, each of which are optionally substituted with oneor more groups independently selected from R^(4X), —O(R^(4X)), R^(5X),—O(R^(5X)), —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH, —C(═O)O(C₁₋₄ alkyl),—C(═O)N(R^(7B))₂, R³ and halo;R^(4A) is a 5 membered monocyclic heteroaryl, optionally substitutedwith one or more groups independently selected from R^(4X), —O(R^(4X)),R^(5X), —O(R^(5X)), —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH, —C(═O)O(C₁₋₄alkyl), —C(═O)N(R^(7B))₂, R³ and halo;each R⁵, R^(5A) and R^(5B) are independently phenyl, each of which areoptionally substituted with one or more groups independently selectedfrom R^(4X), —O(R^(4X)), R^(5X), —O(R^(5X)), —OH, —CN, C₁₋₄ alkoxy,—C(═O)OH, —C(═O)O(C₁₋₄ alkyl), —C(═O)N(R^(7B))₂, R³ and halo;each R^(4X) is independently monocyclic or bicyclic 5 to 9 memberedheteroaryl, each of which are optionally substituted with one or moregroups independently selected from —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH,—C(═O)N(R^(7B))₂, R^(3X) and halo;each R^(5X) is independently phenyl, each of which are optionallysubstituted with one or more groups independently selected from —OH,—CN, C₁₋₄ alkoxy, —C(═O)OH, —C(═O)N(R^(7B))₂, R^(3x) and halo;R⁶ is C₁₋₄ alkoxy optionally substituted with one or more groupsindependently selected from R^(4X), R^(5x) and F;each R⁷, R^(7A), R^(7B) and R^(7C) are independently H, C₁₋₄ alkyl orC₃₋₆ cycloalkyl;R⁸, R^(8A), R^(8B) are independently C₁₋₄ alkyl or C₃₋₆ cycloalkyl, eachof which are optionally substituted with one or more groupsindependently selected from R^(4B), R^(5B), F, —OH, —CN, C₁₋₄ alkoxy,—C(═O)O(C₁₋₄ alkyl) and —C(═O)N(R^(7C))₂;wherein the ring system is a saturated or partly saturated, monocyclic,bicyclic or tricyclic, 4-13 membered ring comprising one N atom, andoptionally one or two further heteroatoms independently selected from N,O and S; andwherein each heteroaryl is independently an aromatic ring containing oneor more heteroatoms independently selected from N, O and S,or a pharmaceutically acceptable salt thereof.

In a further aspect there is provided a pharmaceutical compositioncomprising a compound of Formula (I) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient.

In a further aspect there is provided a compound of Formula (I) or apharmaceutically acceptable salt thereof, for use in therapy.

In a further aspect there is provided a compound of Formula (I) or apharmaceutically acceptable salt thereof, for use in the treatment ofliver disease.

In a further aspect there is provided the use of a compound of Formula(I) or a pharmaceutically acceptable salt thereof, in the manufacture ofa medicament.

In a further aspect there is provided the use of a compound of Formula(I) or a pharmaceutically acceptable salt thereof, in the manufacture ofa medicament for the treatment of liver disease.

In a further aspect there is provided a method of treating liver diseasein a patient comprising administering to the patient an effective amountof a compound of Formula (I) or a pharmaceutically acceptable saltthereof.

In a further aspect there is provided intermediates useful for thesynthesis of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

Definitions

So that the present specification may be more readily understood,certain terms are explicitly defined below. In addition, definitions areset forth as appropriate throughout the detailed description.

As used herein the term “alkyl” refers to both straight and branchedchain saturated hydrocarbon radicals having the specified number ofcarbon atoms.

In this specification the prefix C_(x-y), as used in terms such as“C_(x-y) alkyl” and the like where x and y are integers, indicates thenumerical range of carbon atoms that are present in the group. Examplesof suitable C₁₋₃ alkyl groups include methyl, ethyl, n-propyl, andi-propyl. Examples of suitable C₁₋₄ alkyl groups include methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.

In this specification the prefix X-Y membered, as used in terms such as“X-Y membered ring” and the like where X and Y are integers, indicatesthe numerical range of atoms (i.e. carbon atoms and heteroatoms) thatare present in the group.

As used herein the term “alkoxy” refers to a saturated group comprisingthe specified number of carbon atoms and one oxygen atom. For theavoidance of doubt, the alkoxy group may be a straight chain or abranched chain. Examples of suitable C₁₋₃ alkoxy groups include methoxy(OMe), ethoxy (OEt), n-propoxy (O^(n)Pr) and i-propoxy (O^(i)Pr).Examples of suitable C₁₋₄alkoxy groups include methoxy (OMe), ethoxy(OEt), n-propoxy (O^(n)Pr), i-propoxy (O^(i)Pr), n-butoxy (O^(n)Bu),i-butoxy (O^(i)Bu), s-butoxy (O^(s)Bu) and t-butoxy (O^(t)Bu).

As used herein the term “cycloalkane” refers to a saturated carbocyclicring. Examples of C₃₋₆ cycloalkane groups are cyclopropane, cyclobutane,cyclopentane and cyclohexane.

As used herein the term “cycloalkylidyne” refers to a 1,1-diradical of acycloalkane. Examples of C₃₋₆ cycloalkylidyne are cyclopropylidene

cyclobutylidene

cyclopentylidene

and cyclohexylidene

Unless otherwise stated, “halo” is selected from Cl, F, Br and I. Inembodiments, halo is selected from Cl and F.

The term “heteroatom” refers to N, O or S.

Unless otherwise stated, the term “heteroaryl” is an aromatic,monocyclic or bicyclic, 5 to 9 membered ring containing one or moreheteroatoms independently selected from N, O and S.

Where a compound of the disclosure comprises more than one heteroarylgroups, the heteroaryl groups may be the same or different. A heteroarylmay be a 5 or 6 membered monocyclic heteroaryl. Examples of suitable 5membered heteroaryl groups include pyrrolyl, furanyl, thiophenyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, furazanyl,1,3,4-thiadiazolyl and tetrazolyl. Examples of suitable 6 memberedheteroaryl groups include pyridyl (such as 2-pyridyl, 3-pyridyl or4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,4-triazinyl. Aheteroaryl may be a 9-membered bicyclic heteroaryl. Where a heteroarylis bicyclic, one or both rings may be aromatic. Examples of a suitable 9membered heteroaryl groups include indolyl, isoindolyl, benzofuranyl,isobenzofuranyl, indolinyl, isoindolinyl, benzothiophenyl,isobenzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl,[1,2,4]triazolo[4,3-b]pyridazinyl (such as6-[1,2,4]triazolo[4,3-b]pyridazinyl) and benzo[d]oxazolyl (such as2-benzo[d]oxazolyl).

Unless otherwise stated, the term “heterocycloalkyl” refers to asaturated monocyclic, bicyclic or tricyclic ring comprising one N atom,and one further heteroatom selected from N, O and S. For the avoidanceof doubt, the other atoms of the ring are carbon. Examples of suitableheterocycloalkyl groups include 4-8 membered monocyclicheterocycloalkyl, 8-11 membered spirocyclic bicyclic heterocycloalkyl,7-10 membered fused bicyclic heterocycloalkyl and 8-10 membered bridgedbicyclic heterocycloalkyl.

The term “4-8 membered monocyclic heterocycloalkyl” refers to asaturated, 4-8 membered monocyclic ring comprising one nitrogen atom andoptionally one further heteroatom selected from nitrogen, oxygen andsulfur, For the avoidance of doubt, the other atoms of the ring arecarbon. A suitable 4 membered heterocycloalkyl group is azetidin-1-yl. Asuitable 5 membered heterocycloalkyl group is pyrrolidin-1-yl. Examplesof suitable 6 membered heterocycloalkyl groups include piperidin-1-yl,piperazin-1-yl, morpholin-4-yl and thiomorpholin-4-yl. Examples ofsuitable 7 membered heterocycloalkyl groups include azepan-1-yl,1,4-diazepan-1-yl, 1,4-oxazepan-4-yl and 1,4-thiazepan-4-yl. Examples ofsuitable 8 membered heterocycloalkyl groups include azocan-1-yl,1,4-diazocan-1-yl, 1,5-diazocan-1-yl, 1,4-oxazocan-4-yl,1,5-oxazocan-5-yl, 1,4-thiazocanyl and 1,5-thiazocanyl.

The term “8-11 membered spirocyclic bicyclic heterocydoalkyl” refers toa saturated, 8-11 membered bicyclic, spirocyclic ring comprising onenitrogen atom and optionally one further heteroatom selected from N, Oand S. For the avoidance of doubt, the other atoms of the ring arecarbon. Examples of suitable 8 membered spirocyclic heterocycloalkylgroups include 5-azaspiro[2.5]octan-5-yl, 4,7-diazaspiro[2.5]octan-7-yl,4-oxa-7-azaspiro[2.5]octan-7-yl and 4-thia-7-azaspiro[2.5]octan-7-yl.Examples of suitable 9 membered spirocyclic heterocycloalkyl groupsinclude 6-azaspiro[3.5]nonan-6-yl, 5,8-diazaspiro[3.5]nonan-8-yl,5-oxa-8-azaspiro[3.5]nonan-8-yl and 5-thia-8-azaspiro[3.5]nonan-8-yl.Examples of suitable 10 membered spirocyclic heterocycloalkyl groupsinclude 7-azaspiro[4.5]decan-7-yl, 6,9-diazaspiro[4.5]decan-9-yl,6-oxa-9-azaspiro[4.5]decan-9-yl and 6-thia-9-azaspiro[4.5]decan-9-yl.Examples of suitable 11 membered spirocyclic heterocycloalkyl groupsinclude 2-azaspiro[5.5]undecane-2-yl, 1,4-diazaspiro[5.5]undecan-4-yl,1-oxa-4-azaspiro[5.5]undecan-4-yl and 1-thia-4-azaspiro[5.5]undecan4-yl.

The term “7-10 membered fused bicyclic heterocycloalkyl” refers to asaturated, 7-10 membered bicyclic, fused ring comprising one nitrogenatom and optionally one further heteroatom selected from N, O and S. Forthe avoidance of doubt, the other atoms of the ring are carbon. Examplesof suitable 7 membered fused bicyclic heterocycloalkyl groups include2-azabicyclo[4.1.0]heptan-2-yl, 2,5-diazabicyclo[4.1.0]heptan-2-yl,2-oxa-5-azabicyclo[4.1.0]heptan-5-yl and2-thia-5-azabicyclo[4.1.0]heptan-5-yl. Examples of suitable 8 memberedfused bicyclic heterocycloalkyl groups include2-azabicyclo[4.2.0]octan-2-yl, 2,5-diazabicyclo[4.2.0]octan-2-yl,2-oxa-5-azabicyclo[4.2.0]octan-5-yl and2-thia-5-azabicyclo[4.2.0]octan-5-yl. Examples of suitable 9 memberedfused bicyclic heterocycloalkyl groups includeoctahydro-1H-cyclopenta[b]pyridin-1-yl,octahydro-1H-cyclopenta[b]pyrazin-1-yl,octahydrocyclopenta[b][1,4]oxazin-4-yl andoctahydrocyclopenta[b][1,4]thiazin-4-yl. Examples of suitable 10membered fused bicyclic heterocycloalkyl groups includedecahydroquinolin-1-yl, decahydroquinoxalin-1-yl,octahydro-2H-benzo[b][1,4]oxazin-4-yl andoctahydro-2H-benzo[b][1,4]thiazin-4-yl.

The term “8-10 membered bridged bicyclic heterocycloalkyl” refers to asaturated, 8-10 membered bicyclic, bridged ring comprising one nitrogenatom and optionally one further heteroatom selected from nitrogen,oxygen and sulfur, wherein the remaining atoms of the 8-10 memberedfused bicyclic heterocycloalkyl group are carbon. Examples of a suitable8-10 membered bridged bicyclic heterocycloalkyl groups include3-azabicyclo[3.2.1]octan-3-yl, 3-azabicyclo[3.2.2]nonane and3-azabicyclo[3.3.2]decane-3-yl.

The term “oxo” refers to a oxygen atom forming a double bond (i.e. ═O)to a suitable atom, such as carbon.

Unless otherwise stated, the term “ring system” refers to a saturated orpartly saturated, monocyclic, bicyclic or tricyclic, 4-13 membered ringcomprising one N atom, and optionally one or two further heteroatomsindependently selected from N, O and S. For the avoidance of doubt, theother atoms of the ring are carbon. Where the ring system is bicyclic,it may be spirocyclic, fused or bridged. Examples of suitable monocyclicring systems include 4-6 membered heterocycloalkyl. Examples of suitablebicyclic ring systems include 8-11 membered spirocyclic bicyclicheterocycloalkyl, 7-10 membered fused bicyclic heterocycloalkyl and 8-10membered bridged bicyclic heterocycloalkyl.

The term “saturated or partially saturated” ring system refers to a ringsystem that is aliphatic, or which contains at least one aliphatic ringand one or two aromatic rings.

Unless specifically stated, the bonding of an atom or group may be anysuitable atom of that group; for example, propyl includes prop-1-yl andprop-2-yl.

For the avoidance of doubt, where multiple substituents areindependently selected from a given group, the selected substituents maycomprise the same substituents or different substituents from within thegiven group.

For the avoidance of doubt, the use of a circle within a 5 membered ringindicates that the 5 membered ring is an aromatic ring. By way ofillustration only,

indicates an aromatic ring selected from

For the avoidance of doubt, the use of

in formulas of this specification denotes the point of attachmentbetween different groups. By way of illustration only,

denotes a 3-hydroxyphenyl radical which is attached to a different groupthrough the carbon atom meta- to the OH substituent.

For the avoidance of doubt, the use of a bond between a substituent andthe centre of a ring denotes that the substituent may replace anyhydrogen atom directly attached to the ring, whether that hydrogen atombe attached to a C or N atom. By way of illustration only,

indicates a group selected from

Where any embodiment within this specification includes a group which issaid to be “optionally substituted”, then a further embodiment willinclude that embodiment wherein the said group is unsubstituted.

For the avoidance of doubt, where multiple substituents areindependently selected from a given group, the selected substituents maycomprise the same substituents or different substituents from within thegiven group.

Units, prefixes, and symbols are denoted in their International Systemof Units (SI) accepted form. Numeric ranges are inclusive of the numbersdefining the range.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure is related. For example, the ConciseDictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed.,2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed.,1999, Academic Press; and the Oxford Dictionary of Biochemistry andMolecular Biology, Revised, 2000, Oxford University Press, provide oneof skill with a general dictionary of many of the terms used in thisdisclosure.

DESCRIPTION OF FIGURE

Embodiments and experiments illustrating the principles of thedisclosure will now be discussed with reference to the accompanyingFIGURE in which:

FIG. 1 illustrates the synthesis of Intermediate 1 in flow.

DETAILED DESCRIPTION

In one aspect there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, as defined above.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is analiphatic, monocyclic, bicyclic or tricyclic, 4-13 membered ringcomprising one N atom, and optionally one or two further heteroatomsindependently selected from N, O and S.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is analiphatic, monocyclic or bicyclic, 4-11 membered ring comprising one Natom, and optionally one or two further heteroatoms independentlyselected from N, O and S (wherein the ring system is optionallysubstituted with one or more R^(C)).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is analiphatic, monocyclic or bicyclic, 5-11 membered ring comprising one Natom, and optionally one further heteroatom selected from N, O and S(wherein the ring system is optionally substituted with one or moreR^(C)).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is analiphatic, monocyclic or bicyclic, 5-8 membered ring comprising one Natom, and optionally one further heteroatom selected from N, O and S(wherein the ring system is optionally substituted with one or moreR^(C)).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is analiphatic, monocyclic or bicyclic, 5-11 membered ring comprising one Natom, and one further heteroatom selected from N, O and S (wherein thering system is optionally substituted with one or more R^(C)).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is analiphatic, monocyclic or bicyclic, 5-8 membered ring comprising one Natom, and one further heteroatom selected from N, O and S (wherein thering system is optionally substituted with one or more R^(C)).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is analiphatic, monocyclic or bicyclic, 5-8 membered ring comprising one Natom and one O atom (wherein the ring system is optionally substitutedwith one or more R^(C)).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is analiphatic monocyclic 5-8 membered ring comprising one N atom and one Oatom (wherein the ring system is optionally substituted with one or moreR^(C)).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is a4-8 membered monocyclic heterocycloalkyl, optionally substituted withone or more R^(C).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is a5-7 membered monocyclic heterocycloalkyl, optionally substituted withone or more R^(C).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is an8-11 membered spirocyclic bicyclic heterocycloalkyl, optionallysubstituted with one or more R^(C).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is an7-10 membered fused bicyclic heterocycloalkyl, optionally substitutedwith one or more R^(C).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system is an8-10 membered bridged bicyclic heterocycloalkyl, optionally substitutedwith one or more R^(C).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system isoptionally substituted with one or more R^(C). In further embodiments,the ring system is optionally substituted with one to three R^(C). Infurther embodiments, the ring system is optionally substituted with oneor two R^(C). In further embodiments, the ring system is notsubstituted.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein each R^(C) isindependently selected from F, R³, R⁴, —O(R⁵), —O(R⁵), R⁵, R⁶, —OH, —CNand —C(═O)N(R^(7A))₂. In further embodiments, each R^(C) isindependently selected from R³, R⁴, —O(R⁴), —O(R⁵), R⁵ and R⁶. Infurther embodiments, each R^(C) is independently selected from R³, R⁴and R⁵. In further embodiments, each R^(C) is independently R³. Infurther embodiments, each R^(C) is independently C₁ alkyl, optionallysubstituted with one or more (such as one to three) F. In furtherembodiments, each R^(C) is independently selected from C₁₋₄alkyl, phenyland —O(phenyl). In further embodiments, each R^(C) is independently C₁₋₄alkyl. In further embodiments, each R^(C) is CH₃.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein NR¹R² is a groupselected from

wherein x is selected from 0 to 3, and each R⁹ is independently selectedfrom R³, R⁴ and R⁵.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein NR¹R² is a groupselected from

wherein x is selected from 0 to 3, and each R⁹ is independently selectedfrom R³, R⁴ and R⁵.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein NR¹R² is a groupselected from,

wherein x is selected from 0 to 3, and each R⁹ is independently selectedfrom R³, R⁴ and R⁵.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein NR¹R² is

wherein x is selected from 0 to 3, and each R⁹ is independently selectedfrom R³, R⁴ and R⁵.

In embodiments, the compound of Formula (I) is a compound of Formula(II):

whereinJ is selected from O, S, CH₂, NH and a covalent bond,G is either absent or, together with the carbon atoms to which it isattached, forms a C₃₋₆ cycloalkane ring;Z is such that(i) where G is absent and J is selected from O, S, CH₂ and a covalentbond, Z is selected from CH₂, CH₂CH₂ and C₃₋₆ cycloalkylidyne,(ii) where G is absent and J is NH, Z is selected from CH₂, CH₂CH₂, C₃₋₆cycloalkylidyne and C(═O), and(iii) where G, together with the carbon atoms to which it is attached,forms a C₃₋₆ cycloalkane ring, Z is CH₂;x is selected from 0 to 3; andeach R⁹ is independently selected from R³, R⁴ and R⁵,or a pharmaceutically acceptable salt thereof.

In embodiments, the compound of Formula (II) is a compound of Formula(IIA) or Formula (IIB)

wherein X¹, X², X³, A, J, R⁹ and x are as defined for a compound ofFormula (II).

In embodiments, the compound of Formula (II) is a compound of Formula(IIC)

wherein X¹, X², X³, A, J, R⁹ and x are as defined for a compound ofFormula (II).

In embodiments, the compound of Formula (II) is a compound of Formula(IID)

wherein X¹, X², X³, A, J, R⁹ and x are as are as defined for a compoundof Formula (II), and y is an integer from 1 to 4.

In embodiments, the compound of Formula (II) is a compound of Formula(IIE)

wherein X¹, X², X³, A, J, R⁹ and x are as are as defined for a compoundof Formula (II), and z is an integer from 1 to 4.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein NR¹R² is a groupselected from

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein NR¹R² is a groupselected from

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein NR¹R² is a groupselected from

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein NR¹R² is a groupselected from

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein NR¹R² is a groupselected from

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system isselected from

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system isselected from

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the ring system isselected from

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is selected from R⁸and R^(4A), and R² is selected from R^(8A) and H.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is R⁸, and R² isselected from R^(8A) and H.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₁₋₄ alkyl orC₃₋₆ cycloalkyl (such as C₁₋₄ alkyl), each of which are optionallysubstituted with one or more groups (such as one to three groups)independently selected from R⁴ (such as R^(4x)), R^(5B) (such asR^(5x)), F, —OH, —CN, C₁₋₄ alkoxy, —C(═O)O(C₁₋₄ alkyl) and—C(═O)N(R^(7C))₂. In further embodiments, R⁸ is C₁₋₄ alkyl (such as CH₃)optionally substituted with one or two groups (such as one group)independently selected from R^(4B) (such as R^(4x)), R^(5B) (such asR^(5x)), F, —OH, —CN, C₁₋₄ alkoxy, —C(═O)O(C₁₋₄ alkyl) and—C(═O)N(R^(7C))₂. In further embodiments, R⁸ is C₁₋₄ alkyl (such as CH₃)optionally substituted with one or two groups (such as one group)independently selected from R^(4B) (such as R^(4x)) and R^(5B) (such asR^(5x)). In further embodiments, R⁸ is C₁₋₄ alkyl (such as CH₃)optionally substituted with one or two groups (such as one group)independently selected from monocyclic or bicyclic 5 to 9 memberedheteroaryl (such as a monocyclic 5- or 6-membered heteroaryl) andphenyl, wherein the heteroaryl and phenyl are optionally substitutedwith one or more groups (such as one or two groups) selected from C₁₋₄alkyl (such as CH₃), C₃₋₆ cycloalkyl (such as cyclohexyl) and phenyl.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R⁸ is C₁₋₄ alkyl orC₃₋₆ cycloalkyl (such as C₁₋₄ alkyl), each of which are substituted withone or more groups (such as one to three groups) independently selectedfrom R^(4B) (such as R^(4x)), R^(5B) (such as R^(5x)), F, —OH, —CN, C₁₋₄alkoxy, —C(═O)O(C₁₋₄ alkyl) and —C(═O)N(R^(7C))₂. In furtherembodiments, R⁸ is C₁₋₄ alkyl (such as CH₃) substituted with one or twogroups (such as one group) independently selected from R^(4B) (such asR^(4x)), R^(5B) (such as R^(5x)), F, —OH, —CN, C₁₋₄ alkoxy, —C(═O)O(C₁₋₄alkyl) and —C(═O)N(R^(7C))₂. In further embodiments, R⁸ is C₁₋₄ alkyl(such as CH₃) substituted with one or two groups (such as one group)independently selected from R^(4B) (such as R^(4x)) and R^(5B) (such asR^(5x)). In further embodiments, R⁸ is C₁₋₄ alkyl (such as CH₃)substituted with a either a phenyl or a monocyclic or bicyclic 5 to 9membered heteroaryl, wherein the phenyl or monocyclic or bicyclic 5 to 9membered heteroaryl is optionally substituted with one or two groupsindependently selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl and C₁₋₄ alkoxy.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R^(4A) is 5 memberedmonocyclic heteroaryl optionally substituted with one or more groups(such as one to three groups) independently selected from R^(4X),—O(R^(4X)), R^(5X), —O(R^(5X)), —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH,—C(═O)O(C₁₋₄ alkyl), —C(═O)N(R^(7B))₂, R³ and halo. In furtherembodiments, R^(4A) is 5 membered monocyclic heteroaryl optionallysubstituted with one or two groups independently selected from R^(4X),R^(5X) and R^(3X). In further embodiments, R^(4A) is 5 memberedmonocyclic heteroaryl optionally substituted with one or two groupsselected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl and phenyl. In furtherembodiments, R^(4A) is 1H-pyrazolyl (such as 3-1H-pyrazolyl) tetrazolyl(such as 5-tetrazolyl), pyridyl (such as 2-pyridyl, 3-pyridyl or4-pyridyl) or 1H-benzo[d]imidazolyl (such as 2-1H-benzo[d]imidazole),each of which is optionally substituted with one or more groups (such asone or two groups) selected from C₁₋₄ alkyl (such as CH₃), C₃₋₆cycloalkyl (such as cyclohexyl) and phenyl.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R^(A) is

wherein R¹⁰ is R³ or R^(5x), and X⁴ and X⁵ are independently N or CH. Infurther embodiments, X⁴ is CH.

In further embodiments, X⁵ in CH.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein each R^(4B) isindependently monocyclic or bicyclic 5 to 9 membered heteroaryl,optionally substituted with one or more (such as one to three) groupsindependently selected from R^(4X), —O(R^(4X)), R^(5X), —O(R^(5X)), —OH,—CN, C₁₋₄ alkoxy, —C(═O)OH, —C(═O)O(C₁₋₄ alkyl), —C(═O)N(R^(7B))₂, R³and halo. In further embodiments, each R^(4B) is independentlymonocyclic or bicyclic 5 to 9 membered heteroaryl (such as a monocyclic5- or 6-membered heteroaryl) optionally substituted with one or more(such as one to three) groups independently selected from halo, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy and CN. In further embodiments,R^(4B) is 1H-pyrazolyl (such as 3-1H-pyrazolyl), tetrazolyl (such as5-tetrazolyl), pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl) or1H-benzo[d]imidazolyl (such as 2-1H-benzo[d]imidazole), each of which isoptionally substituted with one or two groups selected from C₁₋₄ alkyl,C₃₋₆ cycloalkyl and phenyl.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R^(8A) is C₁₋₄ alkyl.In further embodiments, R^(8A) is CH₃, CH(CH₃)₂ or C(CH₃)₃.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is R^(5A) and R² isR^(8B).

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R^(5A) is phenyl,optionally substituted with one or more groups (such as one to threegroups) independently selected from —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH,—C(═O)N(R^(7B))₂, R^(3x) and halo. In further embodiments, R^(5A) isphenyl, optionally substituted with one or two groups independentlyselected from —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH, —C(═O)N(R^(7B))₂, R^(3x)and halo. In further embodiments, R^(5A) is phenyl, optionallysubstituted with one or two groups independently selected from —CN, C₁₋₄alkoxy, R^(3x) and halo. In further embodiments, R^(5A) is phenyl,optionally substituted with —CN.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R^(5B) is phenyl,optionally substituted with one or more groups (such as one to threegroups) independently selected from —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH,—C(═O)N(R^(7B))₂, R^(3x) and halo. In further embodiments, R^(5B) isphenyl, optionally substituted with one or two groups independentlyselected from —CN, C₁₋₄ alkoxy, R^(3x) and halo. In further embodiments,R^(5B) is phenyl, optionally substituted with C₁₋₄ alkoxy.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R^(8B) is C₁₋₄ alkyl.In further embodiments, R^(8B) is CH₃, CH(CH₃)₂ or C(CH₃)₃.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein NR¹R² is selected from

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptablesalt thereof, wherein each R^(A) is independently selected from H, halo,R^(X), —OR^(x), and —CN, wherein each R^(X) is independently C₁₋₃ alkyloptionally substituted with one to three F. In further embodiments, eachR^(A) is independently selected from H, halo, C₁₋₃ alkyl, C₁₋₃ alkoxy,CF₃, OCF₃, CHF₂, OCHF₂ and —CN. In further embodiments, each R^(A) isindependently selected from H, F and Cl. In further embodiments, eachR^(A) is independently selected from H and F.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptablesalt thereof, wherein A is selected from

wherein R^(A) is as defined above.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptablesalt thereof, wherein A is

wherein R^(A) and R^(B) are as defined above. In further embodiments,R^(B) is F, Cl or CF₃. In further embodiments, one or more R^(A) is F.In further embodiments, two or more R^(A) is F. In further embodiments,each R^(A) is F.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptablesalt thereof, wherein A is

wherein R^(A) is as defined above. In further embodiments, each R^(A) isindependently H, F or Cl. In further embodiments, each R^(A) is H or F.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptablesalt thereof, wherein A is

wherein R^(E) is H or halo.

In embodiments, there is provided a compound of Formula (I) which is acompound of Formula (III):

whereinJ is selected from O, S, CH₂, NH and a covalent bond,x is selected from 0 to 3;each R⁹ is independently selected from R³, R⁴ and R⁵; andR^(E) is H or halo,or a pharmaceutically acceptable salt thereof.

In embodiments, the compound of Formula (III) is a compound of Formula(IIIA), (IIIB) or (IIIC)

or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³,R^(E), R⁹ and x are as are as defined for a compound of Formula (III).In further embodiments, each R⁹ is independently selected from C₁₋₄alkyl. In further embodiments, x is selected from 1, 2 and 3.

In embodiments, the compound of Formula (III) is a compound of Formula(IIID)

or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³ andR^(E) are as are as defined for a compound of Formula (III), and eachR¹¹ is independently selected from H, R³, R⁴ and R^(5.) In furtherembodiments, each R¹¹ is independently H, R³, R^(4x) or R^(5x). Infurther embodiments, each R¹¹ is independently H, R^(3x), R^(4x) orR^(5X). In further embodiments, each R¹¹ is independently H or R^(3x).In further embodiments, each R¹¹ is independently H or C₁₋₄ alkyl. Infurther embodiments, each R¹¹ is independently H or CH₃.

In embodiments, there is provided a compound of Formula (III), (IIIA),(IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof,wherein R^(E) is H, F or Cl. In further embodiments, R^(E) is H or F.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein one ofX¹, X² and X³ is O and the other two of X¹, X² and X³ are selected fromN and CR^(I). In further embodiments, R^(Y) is H.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein one ofX¹, X² and X³ is S and the other two of X¹, X² and X³ are selected fromN and CR^(Y). In further embodiments, R^(Y) is H.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein one ofX¹, X² and X³ is O and the other two of X¹, X² and X³ are both N.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein one ofX¹, X² and X³ is O, one of X¹, X² and X³ is N, and one of X¹, X² and X³is CR^(Y). In further embodiments, R^(Y) is H or —CN.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein one ofX¹, X² and X³ is S and the other two of X¹, X² and X³ are both N.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein one ofX¹, X² and X³ is S, one of X¹, X² and X³ is N, and one of X¹, X² and X³is CR^(Y). In further embodiments, R^(Y) is H.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein one ofX¹, X² and X³ is S and the other two of X¹, X² and X³ are both CR^(Y).In further embodiments, each R^(Y) is H.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein

-   -   (i) X¹ is N, X² is O and X³ is N,    -   (ii) X¹ is N, X² is N and X³ is O;    -   (iii) X¹ is CR^(Y), X² is CR and X³ is S;    -   (iv) X¹ is O, X² is N and X³ is CR^(Y);    -   (v) X¹ is N, X² is O and X³ is CR^(Y);    -   (vi) X¹ is CR^(Y), X² is N and X³ is O;    -   (vii) X¹ is O, X² is N and X³ is N;    -   (viii) X¹ is N, X² is N and X³ is S; or    -   (ix) X¹ is CR^(Y), X² is S and X³ is CR^(Y).

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein

-   -   (i) X¹ is N, X² is O and X³ is N,    -   (ii) X¹ is N, X² is N and X³ is O;    -   (iii) X¹ is CR^(Y), X² is CR and X³ is S;    -   (iv) X¹ is O, X² is N and X³ is CR^(Y);    -   (v) X¹ is N, X² is O and X³ is CR^(Y);    -   (vi) X¹ is CR^(Y), X² is N and X³ is O;    -   (vii) X¹ is O, X² is N and X³ is N;    -   (viii) X¹ is N, X² is N and X³ is S;    -   (ix) X¹ is CR^(Y), X² is S and X³ is CR^(Y) or    -   (x) X¹ is CR^(Y), X² is N and X³ is S.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein

-   -   (i) X¹ is N, X² is O and X³ is N,    -   (ii) X¹ is N, X² is N and X³ is O;    -   (iii) X¹ is CH, X² is CH and X³ is S;    -   (iv) X¹ is O, X² is N and X³ is CH;    -   (v) X¹ is N, X² is O and X³ is CH;    -   (vi) X¹ is CH, X² is N and X³ is O;    -   (vii) X¹ is O, X² is N and X³ is N;    -   (viii) X¹ is N, X² is N and X³ is S; or    -   (ix) X¹ is CH, X² is S and X³ is CH.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein

-   -   (i) X¹ is N, X² is O and X³ is N,    -   (ii) X¹ is N, X² is N and X³ is O;    -   (iii) X¹ is CH, X² is CH and X³ is S;    -   (iv) X¹ is O, X² is N and X³ is CH;    -   (v) X¹ is N, X² is O and X³ is CH;    -   (vi) X¹ is CH, X² is N and X³ is O;    -   (vii) X¹ is O, X² is N and X³ is N;    -   (viii) X¹ is N, X² is N and X³ is S;    -   (ix) X¹ is CH, X² is S and X³ is CH; or    -   (x) X¹ is CH, X² is N and X³ is S.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein X¹ is N,X² is O and X³ is N.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein X¹ is N,X² is N and X³ is O.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein X¹ is N,X² is N and X³ is S.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein X¹ is N,X² is O and X³ is CR^(Y). In further embodiments, R^(Y) is H or —CN.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein X¹ isCR^(Y), X² is N and X³ is O. In further embodiments, each R^(Y) is H.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or(IIID), or a pharmaceutically acceptable salt thereof, wherein X¹ isCR^(Y), X² is S and X³ is CR^(Y). In further embodiments, each R^(Y) isH.

In embodiments, there is provided a compound of Formula (I) which is acompound of Formula (IV):

x is selected from 0 to 3;each R⁹ is independently selected from R³, R⁴ and R⁵; andR^(E) is H or halo,or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a compound of Formula (I) which is acompound of Formula (V):

x is selected from 0 to 3;each R⁹ is independently selected from R³, R⁴ and R⁵; andR^(E) is H or halo,or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a compound of Formula (I) which is acompound of Formula (VI):

x is selected from 0 to 3;each R⁹ is independently selected from R³, R⁴ and R⁵; andR^(E) is H or halo,or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a compound of Formula (I) which is acompound of Formula (VII):

x is selected from 0 to 3;each R⁹ is independently selected from R³, R⁴ and R⁵; andR^(E) is H or halo,or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a compound of Formula (II), (IIA),(IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV),(V), (VI) or (VII), wherein each R⁹ is independently selected from C₁₋₄alkyl, C₃₋₆ cycloalkyl and phenyl. In further embodiments, each R⁹ isindependently C₁₋₄ alkyl. In further embodiments, each R⁹ is CH₃.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, wherein each R³ is independently C₁₋₄ alkyl or C₃₋₆ cycloalkyl,each of which are optionally substituted with one or more (such as oneto three) groups independently selected from R^(4X), R^(5X), —O(R^(4X)),—O(R^(5X)) and F. In further embodiments, each R³ is independently C₁₋₄alkyl optionally substituted with one to three (such as one or two)groups independently selected from R^(4X), R^(5x) and F. In embodiments,In further embodiments, each R³ is independently C₁₋₄ alkyl, CF₃, CHF₂or CH₂F.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, wherein each R³ is R^(3X).

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, wherein each R^(3X) is independently C₁₋₄ alkyl or C₃₋₆cycloalkyl, each of which are optionally substituted with one or more(such as one to three) F. In further embodiments, each R^(3X) isindependently C₁₋₄ alkyl optionally substituted with one to three F. Infurther embodiments, each R^(3X) is independently Cia alkyl, CF₃, CHF₂or CH₂F. In further embodiments, each R^(3X) is C₁₋₄ alkyl.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, wherein each R⁴ is independently monocyclic or bicyclic 5 to 9membered heteroaryl (such as a monocyclic 5- or 6-membered heteroaryl),each of which are optionally substituted with one or more (such as oneto three) groups independently selected from R^(4X), —O(R^(4X)), R^(5X),—O(R^(5X)), —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH, —C(═O)O(C₁₋₄ alkyl),—C(═O)N(R^(7B))₂, R³ and halo. In further embodiments, each R⁴ isindependently monocyclic or bicyclic 5 to 9 membered (such as amonocyclic 5 or 6 membered heteroaryl) optionally substituted with oneor more (such as one to three) groups independently selected from halo(such as F or Cl), C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄alkoxy and CN. Infurther embodiments, each R⁴ is independently selected from[1,2,4]triazolo[4,3-b]pyridazinyl (such as6-[1,2,4]triazolo[4,3-b]pyridazinyl), pyridyl (such as 2-pyridyl,3-pyridyl or 4-pyridyl), benzo[d]oxazolyl (such as 2-benzo[d]oxazolyl),each of which is optionally substituted with one or more (such as one tothree) groups independently selected from halo (such as F or Cl), C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy and CN.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, wherein each R^(4X) is independently monocyclic or bicyclic 5to 9 membered heteroaryl (such as a monocyclic 5 or 6 memberedheteroaryl), each of which are optionally substituted with one or more(such as one to three) groups independently selected from —OH, —CN, C₁₋₄alkoxy, —C(═O)OH, —C(═O)N(R^(7B))₂, R^(3X) and halo. In furtherembodiments, each R^(4x) is independently monocyclic or bicyclic 5 to 9membered heteroaryl (such as a monocyclic 5- or 6-membered heteroaryl)optionally substituted with one or more (such as one to three) groupsindependently selected from halo (such as F or Cl), C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy and CN. In further embodiments, each R^(4x) isindependently a tetrazolyl (such as 5-tetrazolyl) optionally substitutedwith C₁₋₄ alkyl (such as CH₃).

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, wherein each R⁵ is independently phenyl, optionally substitutedwith one or more (such as one to three) groups independently selectedfrom R^(4X), —O(R^(4X)), R^(3X), —O(R^(3X)), —OH, —CN, C₁₋₄ alkoxy,—C(═O)OH, —C(═O)O(C₁₋₄ alkyl), —C(═O)N(R^(7B))₂, R³ and halo. In furtherembodiments, each R⁵ is independently phenyl optionally substituted withone or more (such as one to three) groups independently selected fromhalo (such as F or Cl), C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy and CN.In further embodiments, each R⁵ is phenyl.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, wherein each R^(5X) is independently phenyl, optionallysubstituted with one or more (such as one to three) groups independentlyselected from —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH, —C(═O)N(R^(7B))₂, R^(3x)and halo. In further embodiments, each R^(5X) is independently phenyloptionally substituted with one or more (such as one to three) groupsindependently selected from halo (such as F or Cl), C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy and CN. In further embodiments, each R^(5X) isphenyl.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, wherein R⁶ is C₁₋₄ alkoxy optionally substituted with one ormore groups (such as one to three groups) independently selected fromR^(4X), R^(5x) and F. In further embodiments, R⁶ is C₁₋₄ alkoxyoptionally substituted with one or more (such as one to three) F. Infurther embodiments, R⁶ is C₁₋₄ alkoxy.

In embodiments, there is provided a compound of Formula (II), (IIA),(IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IV), (V),(VI) or (VII), wherein x is 0, 1, 2 or 3. In further embodiments, x is1, 2 or 3.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), or a pharmaceutically acceptable saltthereof, with the proviso that when A is

and X³ is N, that X¹ is N.

In embodiments, there is provided a compound of Formula (I), (II) or(IIA), or a pharmaceutically acceptable salt thereof, with the provisothat when A is

and X³ is N, that X² is O.

In embodiments, there is provided a compound of Formula (I), (II) or(IIA), or a pharmaceutically acceptable salt thereof, with the provisothat the compound is other than(3-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(3-methylpiperidin-1-yl)methanoneand(3-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(4-methylpiperidin-1-yl)methanone.

In embodiments, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isselected from:

-   (R)-(5-(4-Fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(3-phenylpyrrolidin-1-yl)methanone;-   (3-Phenoxyazetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone;-   (3-(2-Methoxyphenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   N-(1-Cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-5-carboxamide;-   (3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanone-   N-(1-Cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-3-carboxamide;-   (R)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone;-   4-(3-(3-Phenylpyrrolidine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one;-   4-(3-(4-(3-Methoxyphenyl)piperazine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one;-   (R)-(5-(4-Fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone;-   N-(1-Cyclohexyl-1H-pyrazol-5-yl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide;-   5-(4-Fluoro-3-hydroxyphenyl)-3-(3-phenylpyrrolidine-1-carbonyl)isoxazole-4-carbonitrile;-   3-(4-(3-(4-Fluorophenoxy)propyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   3-(4-(3-Methoxyphenyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   5-(2,4,5-Trifluoro-3-hydroxyphenyl)-3-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carbonyl)isoxazole-4-carbonitrile;-   3-(5-Fluoroisoindoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   N-(tert-Butyl)-4-cyano-N-(pyridin-2-ylmethyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxamide;-   3-(3-Cyclopropyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   (S)-3-(3-(4-Chlorophenyl)pyrrolidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   3-((2R,6S)-2,6-Dimethylmorpholine-4-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   3-(4-(Benzo[d]oxazol-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   3-(4-(4-(4-Fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   3-(4-((5-Methoxypyridin-2-yl)oxy)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   3-(4-Hydroxy-4-(trifluoromethyl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   3-(3-Cyclopropyl-3-fluoroazetidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   5-(2,4,5-Trifluoro-3-hydroxyphenyl)-3-(3-(trifluoromethyl)azetidine-1-carbonyl)isoxazole-4-carbonitrile;-   3-(7-Cyano-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;-   2-(5-(2-Bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile;-   2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile;-   (2,2,6,6-Tetramethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone;-   (S)-6-Ethyl-4-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-2-one;-   (3-Isopropylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((3R,5S)-3,5-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((3R,5S)-3,5-Dimethylpiperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((2R,5S)-2,5-Dimethylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   Morpholino(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   Thiomorpholino(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   3-(4-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-2-yl)benzonitrile;-   (8,8-Difluoro-3-azabicyclo[3.2.1]octan-3-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   Piperidin-1-yl(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (6-Oxa-9-azaspiro[4.5]decan-9-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (S)-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2-(trifluoromethyl)morpholino)methanone;-   (2-Isobutylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (3,3-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (R)-(2-(Fluoromethyl)morpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((2R,5R)-2,5-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (R)-(7-Methyl-1,4-oxazepan-4-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (5-Oxa-8-azaspiro[3.5]nonan-8-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (1,9-Dioxa-4-azaspiro[5.5]undecan-4-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((2S,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (4-(4-Methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   4-(1-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperidin-4-yl)benzonitrile;-   (4-(3-(4-Fluorophenoxy)propyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (4-(Pyridin-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   4-(1-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)azetidin-3-yl)benzonitrile;-   (3-Phenylazetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (4-(3-Methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (4-Phenyl-3,6-dihydropyridin-1(2H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   N-(3-Cyanophenyl)-N-methyl-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;-   (3,4-Dihydroisoquinolin-2(1H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (5-Fluoroisoindolin-2-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile;-   (4-(3-Chloro-5-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (4-((5-Methoxypyridin-2-yl)oxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (4-(2-((5-Bromopyridin-2-yl)oxy)ethyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (4-(Pyridin-3-yloxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   N-((5,6-Dimethyl-1H-benzo[d]imidazol-2-yl)methyl)-N-methyl-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;-   (4-(Benzo[d]oxazol-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   N-Methyl-N-((5-methyl-1H-benzo[d]imidazol-2-yl)methyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;-   (3-(4-Fluorophenyl)azetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   N-Isopropyl-N-((3-methylpyridin-2-yl)methyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;-   (3-Propylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (1-Phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   N-(1-(4-Methoxyphenyl)ethyl)-N-methyl-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;-   (3-(4-Fluorophenoxy)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   4-Phenyl-1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperidine-4-carbonitrile;-   (4-Phenylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   2-(4-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-1-yl)benzonitrile;-   4-(4-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-1-yl)benzonitrile;-   (4-(2-Methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   3-(1-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)azetidin-3-yl)benzonitrile;-   2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile;-   ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((2R,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone;-   (5-(4-Fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(5-oxa-8-azaspiro[3.5]nonan-8-yl)methanone;-   5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,3,4-oxadiazole-2-carboxamide;-   5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,2,4-oxadiazole-3-carboxamide;-   (S)-(3-Phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (3-(Benzyloxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (R)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (3-(Benzyloxy)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (R)-(3-Phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   N-(1-Cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxamide;-   N-((1-Cyclohexyl-1H-pyrazol-5-yl)methyl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide;-   (R)-(5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone;-   (3H-Spiro[isobenzofuran-1,3′-pyrrolidin]-1′-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (S)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone;-   N,N-Dimethyl-1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide;-   2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)isoindoline-5-carbonitrile;-   (4-(3-Isopropyl-1,2,4-oxadiazol-5-yl)-3,6-dihydropyridin-1(2H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((2S,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazol-3-yl)methanone;-   2-(5-(2,4,5-Trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile;-   ((2R,6S)-2,6-Dimethylmorpholino)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone;    and-   ((3R,5S)-3,5-Dimethylpiperidin-1-yl)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone.-   In embodiments, there is provided a compound of Formula (I), or a    pharmaceutically acceptable salt thereof, wherein the compound is    selected from:-   ((4aR,7aS)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((4aS,7aR)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((4aR,7aR)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((4aS,7aS)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (5-(3,4-Difluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone;-   (5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2,2,6-trimethylmorpholino)methanone;-   (4-Oxa-7-azaspiro[2.5]octan-7-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   ((3R,5S)-3,5-Dimethylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;    and-   ((2R,6S)-2,6-Dimethylmorpholino)(2-(2,4,5-trifluoro-3-hydroxyphenyl)thiazol-5-yl)methanone.-   In embodiments, there is provided a compound of Formula (I), or a    pharmaceutically acceptable salt thereof, wherein the compound is    selected from:-   rac-((2R,6S)-2-Ethyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   rac-((2R,6S)-2-isopropyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;-   (6-Methyl-5-oxa-8-azaspiro[3.5]nonan-8-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;    and-   (5-(2-Bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone.

A further feature is any of the embodiments described in thespecification with the proviso that any of the specific Examples areindividually disclaimed. A further feature is any of the embodimentsdescribed in the specification with the proviso that any one or more ofthe compounds selected from the above list of Examples of compounds ofthe specification are individually disclaimed.

The compounds disclosed herein may contain one or more chiral centers.Accordingly, if desired, such compounds can be prepared or isolated aspure stereoisomers, i.e. as individual enantiomers, diastereoisomers, oras a stereoisomerically enriched mixture. All such stereoisomer (andenriched) mixtures are included within the scope of the embodiments,unless otherwise stated. Pure stereoisomers (or enriched mixtures) maybe prepared using, for example, optically active starting materials orstereoselective reagents well-known in the art. Alternatively, racemicmixtures of such compounds can be separated using, for example, chiralcolumn chromatography, chiral resolving agents and the like.

Unless stereochemistry is explicitly indicated in a chemical structureor chemical name, the chemical structure or chemical name is intended toembrace all possible stereoisomers, diastereoisomers, conformers,rotamers and tautomers of the compound depicted. For example, a compoundcontaining a chiral carbon atom is intended to embrace both the (R)enantiomer and the (S) enantiomer, as well as mixtures of theenantiomers, including racemic mixtures; and a compound containing twochiral carbons is intended to embrace all enantiomers anddiastereoisomers including (R,R), (S,S), (R,S) and (S,R).

In embodiments, there is provided a pharmaceutical composition whichcomprises a compound of the Formula (I), (II), (IIA), (IIB), (IIC),(IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or(VII), or a pharmaceutically acceptable salt thereof, in associationwith a pharmaceutically acceptable excipient, optionally furthercomprising one or more of the other stereoisomeric forms of the compoundof Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA),(IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII) or pharmaceuticallyacceptable salt thereof, wherein the compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable saltthereof is present within the composition with an enantiomeric excess (%ee) of >90% and a diastereomeric excess (% de) of >90%.

The compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE),(III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), andpharmaceutically acceptable salts thereof, may be prepared, used orsupplied in amorphous form, crystalline form, or semicrystalline formand any given compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID),(IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII),or pharmaceutically acceptable salt thereof, may be capable of beingformed into more than one crystalline/polymorphic form, includinghydrated (e.g. hemi hydrate, a mono hydrate, a di hydrate, a tri hydrateor other stoichiometry of hydrate) and/or solvated forms. It is to beunderstood that the present specification encompasses any and all suchsolid forms of the compound of Formula (I), (II), (IIA), (IIB), (IIC),(IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or(VII), and pharmaceutically acceptable salts thereof.

In further embodiments there is provided a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable saltsthereof, which is obtainable by the methods described in the ‘Examples”section hereinafter.

The present specification is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes will be understood toinclude those atoms having the same atomic number but different massnumbers. For example, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include ¹³C and ¹⁴C. Isotopes of nitrogeninclude ¹⁵N. Isotopes of fluorine include ¹⁸F.

A suitable pharmaceutically acceptable salt of a compound of Formula(I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB),(IIIC), (IIID), (IV), (V), (VI) or (VII) is, for example, a baseaddition salt. A base addition salt of a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII) may be formed by bringing the compoundinto contact with a suitable inorganic or organic base under conditionsknown to the skilled person. A base addition salt may for example be analkali metal salt (such as a sodium, potassium, or lithium salt) or analkaline earth metal salt (such as a calcium salt), which may be formedusing an alkali metal or alkaline earth metal hydroxide or alkoxide(e.g., an ethoxide or methoxide). A base addition salt may also beformed using a suitably basic organic amine (e.g., a choline ormeglumine salt).

A suitable pharmaceutically acceptable salt of a compound of Formula(I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB),(IIIC), (IIID), (IV), (V), (VI) or (VII) is, for example, an acidaddition salt. An acid addition salt of a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII) may be formed by bringing the compoundinto contact with a suitable inorganic or organic acid under conditionsknown to the skilled person. An acid addition salt may for example beformed using an inorganic acid selected from hydrochloric acid,hydrobromic acid, sulphuric acid and phosphoric acid. An acid additionsalt may also be formed using an organic acid selected fromtrifluoroacetic acid, citric acid, maleic acid, oxalic acid, aceticacid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaricacid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonicacid and para-toluenesulfonic acid.

A further suitable pharmaceutically acceptable salt of a compound ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA),(IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) is, for example, a saltformed within a patient's body after administration of a compound ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA),(IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) to the patient.

The compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE),(III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), orpharmaceutically acceptable salt thereof, may be prepared as aco-crystal solid form. It is to be understood that a pharmaceuticallyacceptable co-crystal of an compound of Formula (I), (II), (IIA), (IIB),(IIC), (IIID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V),(VI) or (VII), or pharmaceutically acceptable salts thereof, form anaspect of the present specification.

In a further aspect there is provided a pharmaceutical compositioncomprising a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID),(IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII),or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.

The term “pharmaceutical composition” refers to a preparation which isin such form as to permit the biological activity of the activeingredient, and which contains no additional components which areunacceptably toxic to a patient to which the composition would beadministered. Such compositions can be sterile. A pharmaceuticalcomposition according to the present specification will comprise acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III),(IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. For example, the composition may be in a formsuitable for oral use (for example as tablets, lozenges, hard or softcapsules, aqueous or oily suspensions, emulsions, dispersible powders orgranules, syrups or elixirs) or for parenteral administration (forexample as a sterile aqueous or oily solution for intravenous,subcutaneous, intramuscular or intramuscular dosing or as a suppositoryfor rectal dosing). Such compositions may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents. An effective amount of the compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, will normally be present in the composition.

The compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE),(III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or apharmaceutically acceptable salt thereof, will normally be administeredvia the oral route though parenteral, intravenous, intramuscular,subcutaneous or in other injectable ways, buccal, rectal, vaginal,transdermal and/or nasal route and/or via inhalation, in the form ofpharmaceutical preparations comprising the active ingredient or apharmaceutically acceptable salt or solvate thereof, or a solvate ofsuch a salt, in a pharmaceutically acceptable dosage form may bepossible. Depending upon the disorder and patient to be treated and theroute of administration, the compositions may be administered at varyingdoses.

The pharmaceutical formulations of the compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII) described above may be prepared e.g.for parenteral, subcutaneous, intramuscular or intravenousadministration.

The pharmaceutical formulations of the compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII) described above may conveniently beadministered in unit dosage form and may be prepared by any of themethods well-known in the pharmaceutical art, for example as describedin Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, PA., (1985).

Pharmaceutical formulations suitable for oral administration maycomprise one or more physiologically compatible carriers and/orexcipients and may be in solid or liquid form. Tablets and capsules maybe prepared with binding agents; fillers; lubricants; and surfactants.Liquid compositions may contain conventional additives such assuspending agents; emulsifying agents; and preservatives Liquidcompositions may be encapsulated in, for example, gelatin to provide aunit dosage form. Solid oral dosage forms include tablets, two-piecehard shell capsules and soft elastic gelatin (SEG) capsules. Anexemplary oral composition would comprise a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII) and at least one pharmaceuticallyacceptable excipient filled into a two-piece hard shell capsule or asoft elastic gelatin (SEG) capsule.

As a result of their 17BHSD13 inhibitory activity, the compounds ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA),(IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), and pharmaceuticallyacceptable salts thereof are expected to be useful in therapy, forexample in the treatment of diseases or medical conditions mediated atleast in part by 17BHSD13, including liver disease, such as NASH.

In one aspect of the present specification there is provided a compoundof Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA),(IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceuticallyacceptable salt thereof, for use in therapy.

In one aspect of the present specification there is provided a compoundof Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA),(IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of liver disease. Inembodiments, the liver disease is selected from alcoholic liver disease,non-alcoholic liver disease, NAFLD (such as NASH, liver fibrosis,cirrhosis, and isolated steatosis), liver inflammation, alcoholicsteatoheptatis (ASH), hepatitis C virus (HCV) and hepatocellularcarcinoma (HCC).

The term “therapy” is intended to have its normal meaning of dealingwith a disease in order to entirely or partially relieve one, some orall of its symptoms, or to correct or compensate for the underlyingpathology. The term “therapy” also includes “prophylaxis” unless thereare specific indications to the contrary. The terms “therapeutic” and“therapeutically” should be interpreted in a corresponding manner.

The term “prophylaxis” is intended to have its normal meaning andincludes primary prophylaxis to prevent the development of the diseaseand secondary prophylaxis whereby the disease has already developed andthe patient is temporarily or permanently protected against exacerbationor worsening of the disease or the development of new symptomsassociated with the disease.

The term “treatment” is used synonymously with “therapy”. Similarly theterm “treat” can be regarded as “applying therapy” where “therapy” is asdefined herein.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in providing an inhibitory effect on 17βHSD13.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of a disease mediated by 17βHSD13,such as liver disease (e.g. NASH).

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of fatty liver disease.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of nonalcoholic Fatty Liver Disease(NAFLD), such as isolated steatosis, Nonalcoholic Steatohepatitis(NASH), liver fibrosis or cirrhosis. In further embodiments, the liverdisease is end stage liver disease.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of liver disease, such as NASH,wherein the patient is also suffering from or susceptible to one or moreconditions selected from the group consisting of obesity, dyslipidemia,insulin resistance, Type 2 diabetes, and renal insufficiency.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of liver disease, such as NASH,wherein the patient has a body mass index (BMI) of 27 kg/m² to 40 kg/m².In further embodiments, the subject has a BMI of 30 kg/m² to 39.9 kg/m².In further embodiments, the patient has a BMI of at least 40 kg/m². Infurther embodiments, the patient is overweight. In further embodiments,the patient is obese.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of liver disease, such as NASH,wherein the patient is also suffering from or susceptible todyslipidemia.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of liver disease, such as NASH,wherein the patient is also suffering from or susceptible to insulinresistance.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of liver disease, such as NASH,wherein the patient is also suffering from or susceptible to Type 2diabetes.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of liver disease, such as NASH,wherein the patient is also suffering from or susceptible to renalinsufficiency.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of liver disease, such as NASH,wherein the patient is also suffering from or susceptible to liverfibrosis. In further embodiments, the patient is (i) suffering from orsusceptible to liver fibrosis, and (ii) suffering from or susceptible toone or more conditions selected from the group consisting of obesity,dyslipidemia, insulin resistance, Type 2 diabetes, and renalinsufficiency.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of liver disease, such as NASH,wherein the patient is also suffering from or susceptible to cirrhosis.In further embodiments, the patient is (i) suffering from or susceptibleto cirrhosis, and (ii) suffering from or susceptible to one or moreconditions selected from the group consisting of obesity, dyslipidemia,insulin resistance, Type 2 diabetes, and renal insufficiency.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of NAFLD. In further embodiments, theNAFLD is Stage 1 NAFLD. In further embodiments, the NAFLD is Stage 2NAFLD. In further embodiments, the NAFLD is Stage 3 NAFLD. In furtherembodiments, the NAFLD is Stage 4 NAFLD. See, e.g., “The Diagnosis andManagement of Nonalcoholic Fatty Liver Disease: Practice Guidance Fromthe American Association for the Study of Liver Diseases,” Hepatology,Vol. 67, No. 1, 2018.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of NAFLD, such as NASH. In furtherembodiments, the patient is obese. In further embodiments, the patienthas alcoholic liver disease. In further embodiments, the patient has agenetic risk factor for liver disease, such as the (rs738409 C>G)variant in PNPLA3.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of NASH. In further embodiments, theNASH is Stage 1 NASH. In further embodiments, the NASH is Stage 2 NASH.In further embodiments, the NASH is Stage 3 NASH. In furtherembodiments, the NASH is Stage 4 NASH. In further embodiments, thepatient is also suffering from or susceptible to one or more conditionsselected from obesity, dyslipidemia, insulin resistance, Type 2diabetes, and renal insufficiency.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of liver fibrosis. In furtherembodiments, the liver fibrosis is Stage 3 liver fibrosis. In furtherembodiments, the patient is also suffering from or susceptible to one ormore conditions selected from obesity, dyslipidemia, insulin resistance,Type 2 diabetes, and renal insufficiency.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of cirrhosis. In further embodiments,the cirrhosis is stage F4 cirrhosis. In further embodiments, the patientis also suffering from or susceptible to one or more conditions selectedfrom obesity, dyslipidemia, insulin resistance, Type 2 diabetes, andrenal insufficiency.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of liver inflammation. In furtherembodiments, the inflammation is chronic inflammation. In furtherembodiments, the chronic inflammation is selected from the groupconsisting of rheumatoid arthritis, osteoarthritis, and Crohn's disease.In further embodiments, the chronic inflammation is rheumatoidarthritis.

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of hepatocellular carcinoma (HCC).

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of alcoholic steatoheptatis (ASH).

In embodiments, there is provided a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, for use in the treatment of hepatitis C virus (HCV).

In one aspect of the present specification there is provided the use ofa compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE),(III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or apharmaceutically acceptable salt thereof, as described herein, in themanufacture of a medicament, such as a medicament for the treatment ofdisease (e.g. NASH).

In one aspect of the present specification there is provided a method oftreating disease, such as NASH, in a patient comprising administering tothe patient an effective amount of a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof.

Terms such as “treating” or “treatment” refer to both (1) therapeuticmeasures that cure, slow down, lessen symptoms of, and/or haltprogression of a diagnosed pathologic condition or disorder and (2)prophylactic or preventative measures that prevent and/or slow thedevelopment of a targeted pathologic condition or disorder. Thus, thosein need of treatment include those already with the disorder; thoseprone to have the disorder; and those in whom the disorder is to beprevented.

The term “effective amount” means an amount of an active ingredientwhich is sufficient enough to significantly and positively modify thesymptoms and/or conditions to be treated (e.g., provide a positiveclinical response). The effective amount of an active ingredient for usein a pharmaceutical composition will vary with the particular conditionbeing treated, the severity of the condition, the duration of thetreatment, the nature of concurrent therapy, the particular activeingredient(s) being employed, the particular pharmaceutically-acceptableexcipient(s)/carrier(s) utilized, and like factors within the knowledgeand expertise of the attending physician.

The term “patient” refers to any animal (e.g., a mammal), including, butnot limited to humans, non-human primates, rodents, and the like, whichis to be the recipient of a particular treatment.

Typically, the term “patient” refers to a human subject.

In embodiments, there is provided a method of treating disease in apatient comprising administering to the patient an effective amount of acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III),(IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or apharmaceutically acceptable salt thereof, wherein the disease isselected from isolated steatosis, NASH, liver fibrosis and cirrhosis.

In embodiments, there is provided a method of treating a 17βHSD13mediated disease in a patient comprising administering to the patient aneffective amount of a compound of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V),(VI) or (VII), or a pharmaceutically acceptable salt thereof, such asNASH.

The compounds of the present disclosure may be used in the methodsdescribed above as either as single pharmacological agents or incombination with other pharmacological agents or techniques.

Such combination therapies may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. These combination therapies (and corresponding combinationproducts) employ the compounds of the present disclosure and the otherpharmacological agent(s).

In embodiments, there is provided a combination for use in the treatmentof liver disease, such as NASH, comprising a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, and a sodium-glucose transport protein 2 (SGLT2) inhibitor. Infurther embodiments, the SGLT2 inhibitor is selected from canagliflozin,dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin,luseogliflozin, and remogliflozin.

In embodiments, there is provided a combination for use in the treatmentof liver disease, such as NASH, comprising a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, and metformin, or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a combination for use in the treatmentof liver disease, such as NASH, comprising a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, and a glucagon-like peptide-1 receptor (GLP1) agonist. Infurther embodiments, the GLP1 agonist is selected from exenatide,liraglutide, lixisenatide, albiglutide, dulaglutide, and semaglutide.

In embodiments, there is provided a combination for use in the treatmentof liver disease, such as NASH, comprising a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, and a dipeptidyl peptidase 4 (DPP4) inhibitor. In furtherembodiments, the DPP4 inhibitor is selected sitagliptin, vildagliptin,saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin,alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, anddutogliptin.

In embodiments, there is provided a combination for use in the treatmentof liver disease, such as NASH, comprising a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, and a PPAR agonist. In further embodiments, the PPAR agonist isa PPARα agonist. In further embodiments, the PPAR agonist is a PPARγagonist. In further embodiments, the PPAR agonist is a PPARα/γ agonist.In further embodiments, the PPAR agonist is selected from clofibrate,gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate. In furtherembodiments, the PPAR agonist is a thiazolidinedione. In furtherembodiments, the thiazolidinedione is selected from pioglitazone,rosiglitazone, lobeglitazone, and rivoglitazone. In further embodiments,the PPAR agonist stimulates liver expression of FGF21.

In embodiments, there is provided a combination for use in the treatmentof liver disease, such as NASH, comprising a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, and a Pan-PPAR agonist. In further embodiments, the Pan-PPARagonist is lanifibranor.

In embodiments, there is provided a combination for use in the treatmentof liver disease, such as NASH, comprising a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, and a ThrB agonist. In further embodiments, the ThrB agonist isresmetirom.

In embodiments, there is provided a combination for use in the treatmentof liver disease, such as NASH, comprising a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC),(IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, and a FXR agonist. In further embodiments, the FXR agonist isobeticholic acid.

Although the compounds of the Formula (I), (II), (IIA), (IIB), (IIC),(IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or(VII) are primarily of value as therapeutic agents for use in patients,they are also useful whenever it is required to inhibit 17βHSD13. Thus,they are useful as pharmacological standards for use in the developmentof new biological tests and in the search for new pharmacologicalagents.

In one aspect of the present specification there is providedintermediates and methods useful for the synthesis of compounds ofFormula (I), and pharmaceutically acceptable salts thereof. SchemesP1-P10 disclose intermediates and methods useful for the synthesis ofcompounds of Formula (I), wherein X¹, X², X³, R¹, R² and A are definedas for a compound of Formula (I) herein, LG is a leaving group (e.g. Cl,Br or 1), B¹ is a boronic acid, or a derivative thereof (e.g. a boronicacid, boronate ester or trifluoroborate) and, unless other stated, R^(P)is a C₁₋₄ alkyl group.

A compound of Formula (I) may be formed by reaction of a carboxylic acidof formula (P1.2) with an amine of Formula (P1.3), or a salt thereof(e.g. a HCl salt), in presence of a coupling reagent (such as DIC, EDC,COMU, TBTU or HATU) in the presence of a base (such as DIPEA or2,6-lutidine) in a solvent (such as DMF, MeCN, EtOAc or mixturesthereof), optionally at a temperature range 18 to 60° C. Optionally, thereaction may be performed in presence of HOBt. A compound of Formula(P1.2) may be formed by hydrolysis of an ester of Formula (P1.1) bystandard methods. For esters such as Me or Et, the hydrolysis may beperformed using a base (such as LiOH or NaOH) in a solvent (such as H₂O,MeOH, THF or mixtures thereof), optionally at a temperature in the range18 to 60° C. For acid labile esters (e.g. ^(t)Bu) the hydrolysis may beperformed using an acid (e.g. TFA), either neat or in a solvent (such asDCM or H₂O), optionally at 18° C.

A compound of Formula (I) may also be formed by reaction of an ester ofFormula (P1.1), in which R^(P) is Me or Et, with an amine of Formula(P1.3) optionally in the presence of AlMe₃ or DABAL-Me₃ in a solvent(such as toluene or DMF), optionally at a temperature in the range 18 to70° C. (such as 50 to 70° C.).

A compound of Formula (P2.4) may be formed by reaction of a compound ofFormula (P2.2) with a compound of Formula (P2.3) (where R^(P) is Me orEt), optionally in pyridine, optionally at a temperature of 18 to 50° C.A compound of Formula (P2.2) may be formed from nitriles of Formula(P2.1) by reaction with hydroxylamine (or a salt thereof, e.g. HCl) in asolvent (such as H₂O, MeOH or EtOH or mixtures thereof), optionally at atemperature in the range 50 to 80° C. If a hydroxylammonium salt (e.g.HCl) is used, an additional base (e.g. NaHCO₃) may be added.

A compound of Formula (P3.3) may be formed by reaction of a compound ofFormula (P3.1) and a compound of Formula (P3.2), with EDC and a base(e.g. NaHCO₃), optionally in DMF, optionally at a temperature of 100° C.Optionally, R^(P) is Me or Et.

A compound of Formula (P4.4), in which R^(P) is Me or Et, may be formedby reaction of a compound of Formula (P4.3) by reaction with adehydrating reagent (e.g. POCl₃, SOCl₂ or EDC), either neat or in asolvent (such as toluene or DCM), optionally at a temperature in therange 18 to 90° C., optionally in presence of a base (such as pyridine).A compound of Formula (P4.3) may be formed by reaction of a hydrazide ofFormula (P4.1) with a compound of Formula (P4.2) in a solvent (such asdioxane, THF, DCM or mixtures thereof), optionally at a temperature of 0to 18° C., optionally in presence of a base (such as TEA or DIPEA).

A compound of Formula (5.1) may be reacted with a compound of Formula(P5.2). The reaction may be performed with a Pd-reagent (e.g. XPhos PdG3) in presence of H₂O and a base (e.g. K₃PO₄) in a solvent (such asdioxane, THF or mixtures thereof), optionally at 60° C.

A compound of Formula (P6.3) may be formed by reacting a compound ofFormula (P6.2) with a compound of Formula (P6.1). The reaction may becatalyzed by a Pd-reagent (e.g. Pd-118) in presence of a base (e.g.Cs₂CO₃, K₂CO₃ or Na₂CO₃) and H₂O in a solvent (such as dioxane, THF,EtOH, DMF or mixtures thereof), optionally at a temperature of 60° C.Alternatively, a compound of Formula (P6.3) may be formed by reaction ofa compound of Formula (P6.4) with a compound of Formula (P6.5), whereinLG is optionally Br. The reaction may be catalyzed by a Pd-reagent (e.g.Pd-118) in presence of a base (e.g. K₂CO₃) and H₂O in a solvent (such as1,4-dioxane), optionally at temperature in the range 50 to 80° C.

A compound of Formula (P7.3) may be formed by reaction of an alkyne ofFormula (P7.2) with ethyl (Z)-2-chloro-2-(hydroxyimino)acetate inpresence of a base (e.g. TEA) in a solvent (such as DCM), optionally ata temperature in the range 18 to 45° C. A compound of Formula (P7.2) maybe formed by reaction of an aldehyde of Formula (P7.1) with dimethyl(1-diazo-2-oxopropyl)phosphonate in presence of a base (e.g. K₂CO₃) in asolvent (such as MeOH), optionally at rt.

Alternatively, a compound of Formula (P7.3) may be formed by reaction ofa di-ketone of Formula (P7.5) with hydroxylammonium chloride in asolvent (e.g. EtOH, acetic acid or formic acid), optionally at atemperature in the range 50 to 100° C. A di-ketone of Formula (P7.5) maybe formed by reaction of a methyl ketone of Formula (P7.4) with a base(e.g. LiHMDS or NaOEt) and diethyl oxalate in a solvent (such as THF),optionally at a temperature in the range −78° C. to 18° C.

A compound of Formula (P8.4), where R^(P)=Et, may be formed from acompound of Formula (P8.2) by reaction with a compound of Formula (P8.3)in the presence of a base (e.g. TEA) in a solvent (such as EtOH),optionally at room temperature. A compound of Formula (P8.2) may beformed from an ester of Formula (P8.1) by reaction with MeCN and astrong base (e.g. NaH) in a solvent (e.g THF), optionally at atemperature in the range 18 to 50° C.

A compound of Formula (P9.4) in which R^(P) is Me or ^(t)Bu, may beformed from a compound of Formula (P9.2) by reaction with a compound ofFormula (P9.3) and OXONE (potassium peroxymonosulfate) in the presenceof KCl in a solvent (such as H₂O or aqueous MeCN), optionally at atemperature in the range 0 to 18° C. A compound of Formula (P9.2) may beformed from an aldehyde of Formula (P9.1) by reaction with hydroxylamineor a salt thereof (e.g. HCl) in a solvent (e.g. H₂O, MeOH or EtOH ormixtures thereof), optionally at a temperature in the range 0 to 18° C.If a hydroxylammonium salt (e.g. HCl) is used an additional base (e.g.NaOH, NaOAc or Na₂CO₃) may be added.

A compound of Formula (P10.4), where R^(P) is Me or Et, may be formedfrom a compound of Formula (P10.2) by reacting with a compound ofFormula (P10.3) in a solvent (such as toluene), optionally at atemperature in the range 105 to 110° C. A compound of Formula (P10.2)may be formed by reacting a primary amide of Formula (P10.1) withLawesson's reagent in a solvent (e.g. THF), optionally at a temperaturein the range 18 to 65° C.

It is understood that organic reactions described herein are performedaccording to laboratory practice known to person skilled in the art. Itis understood that some of the reactions described herein may optionallybe performed in different orders than laid out herein. It is understoodthat chiral isomers of compounds herein can be resolved at any stage inthe synthetic process using chiral resolving agents described in theliterature and known to person skilled in the art, or using chiralchromatography methods described in the literature and known to personskilled in the art, or as described further in the Examples.

It is understood that additional and/or other protective groups mayoptionally be needed in some of the steps described above, and it isfurther understood that a deprotection step therefore optionally may beperformed, using method described in the literature and known to personskilled in the art. The protection and deprotection of functional groupsis described in “Protective Groups in Organic Synthesis” 3rd Ed, T. W.Greene and P. G. M. Wutz, Wiley-Interscience (1999), which isincorporated herein by reference.

EXAMPLES

The specification will now be illustrated by the following non-limitingExamples in which, generally:

-   -   (i) operations were carried out at room temperature (rt), i.e.        in the range 17 to 28° C. and where needed under an atmosphere        of an inert gas such as N₂;    -   (ii) where reactions refer to being degassed or purged, this can        be performed for example by purging the reaction solvent with a        constant flow of nitrogen for a suitable period of time (for        example 5 to 10 min) or by repeatedly evacuating the vessel and        backfill with appropriate inert atmosphere (for example        nitrogen (g) or argon (g));    -   (iii) where reactions refer to the use of a microwave reactor,        one of the following microwave reactors were used: BIOTAGE        INITIATOR, PERSONAL CHEMISTRY EMRYS OPTIMIZER, PERSONAL        CHEMISTRY SMITH CREATOR or CEM EXPLORER;    -   (iv) in general, the course of reactions was followed by thin        layer chromatography (TLC) and/or analytical high performance        liquid chromatography (HPLC or UPLC) which was usually coupled        to a mass spectrometer (LCMS).    -   (v) when necessary, organic solutions were dried over anhydrous        MgSO₄ or Na₂SO₄, or passed through a phase-separator using        ISOLUTE Phase Separator, and workup procedures were carried out        using traditional phase separating techniques. When a drying        agent such as e.g. MgSO₄ or Na₂SO₄ is used for drying an organic        layer, it is understood that said organic layer is filtered        before concentration of said layer.    -   (vi), evaporations were carried out either by rotary evaporation        in vacuo or in a GENEVAC HT-4/EZ-2 or BIOTAGE V10;    -   (vii) unless otherwise stated, flash column chromatography was        performed on straight phase silica, using either MERCK Silica        Gel (Art. 9385) or prep-packed cartridges such as BIOTAGE SNAP        cartridges (40-63 μm silica, 4-330 g), BIOTAGE Sfar Silica HC D        cartridges (20 μm, 10-100 g), INTERCHIM PURIFLASH cartridges (25        μm, 4-120 g), INTERCHIM PURIFLASH cartridges (50 μm, 25-330 g),        GRACE GRACERESOLV Silica Flash Cartridges (4-120 g) or AGELA        Flash Colum Silica-CS cartridges (80-330 g), or on reversed        phase silica using AGELA TECHNOLOGIES C-18, spherical cartridges        (20-35 μm, 100 A, 80-330 g), manually or automated using a GRACE        REVELERIS X2 Flash system or similar system;    -   (viii) preparative reverse phase HPLC and preparative reverse        phase SFC were performed using standard HPLC and SFC        instruments, respectively, equipped with either a MS and/or UV        triggered fraction collecting instrument, using either isocratic        or a gradient of the mobile phase as described in the        experimental section and using one of the following methods:        PrepMethod A: The compound was purified by preparative HPLC on a        WATERS SUNFIRE C18 ODB column (5 μm, 150×19 mm ID) using a        gradient of MeCN in H₂O/FA (0.1 M) as mobile phase; PrepMethod        B: The compound was purified by preparative HPLC on a XBRIDGE        C18 ODB column (5 μm, 150×30 mm ID) using a gradient of MeCN in        H₂O/NH₄HCO₃ (10 mM) as mobile phase; PrepMethod C: The compound        was purified by preparative HPLC on a KROMASIL C8 column (10 μm,        250×20 mm ID) using a gradient of MeCN in H₂O/MeCN/FA (95/5/0.2)        as mobile phase; PrepMethod D: The compound was purified by        preparative HPLC on a KROMASIL C8 column (10 μm, 250×50 mm ID)        using a gradient of MeCN in H₂O/MeCN/FA (95/5/0.2) as mobile        phase; PrepMethod E: The compound was purified by preparative        HPLC on a WATERS SUNFIRE C18 ODB column (5 μm, 150×30 mm ID)        using a gradient of MeCN in H₂O/FA (0.1 M) as mobile phase;        PrepMethod F: The compound was purified by preparative HPLC on a        Waters HSS C18 column (5 μm, 100×10 mm ID) using a gradient of        MeCN in H₂O/FA (0.1M) as mobile phase; PrepMethod G: The        compound was purified by preparative HPLC on a WATERS SUNFIRE        C18 column (5 μm, 100×10 mm ID) using a gradient of MeCN in        H₂O/FA (0.1 M, pH3) as mobile phase; PrepMethod H: The compound        was purified by preparative HPLC on a WATERS XBRIDGE C18 column        (5 μm, 100×10 mm ID) using a gradient of MeCN in a H₂O/NH₃        (0.2%, pH 10) as mobile phase; PrepMethod I: The compound was        purified by preparative HPLC on a WATERS XSELECT CSH Fluoro        Phenyl column, (5 μm, 100×10 mm ID) using a gradient of MeCN in        H₂O/FA (0.1M) as mobile phase; PrepMethod J: The compound was        purified by preparative HPLC on a XBRIDGE C18 column (10 μm,        250×50 mm ID) using a gradient of MeCN in H₂O/MeCN/NH₃        (95/5/0.2) as mobile phase; PrepMethod K: The compound was        purified by preparative HPLC on a XBRIDGE Prep OBD C18 column,        (5 μm, 30×150 mm) using a gradient of MeCN in H₂O/FA (0.1%) as        mobile phase; PrepMethod L: The compound was purified by        preparative HPLC on a YMC-ACTUS TRIART C18 column, (5 μm,        30×250 mm) using a gradient of MeCN in H₂O/NH₃ (0.05%) as mobile        phase; PrepMethod M: The compound was purified by preparative        HPLC on a WATERS XSELECT CSH Fluoro Phenyl column, (5 μm, 100×10        mm ID) using a gradient of MeCN in H₂O/TFA (0.05%) as mobile        phase; PrepMethod N: The compound was purified by preparative        HPLC on a WATERS XSELECT CSH OBD column, (5 μm, 150×30 mm ID)        using a gradient of MeCN in H₂O/FA (0.1%) as mobile phase;        PrepMethod O: The compound was purified by preparative HPLC on a        YMC-Actus Triart C18 ExRS column, (5 μm, 30×150 mm) using a        gradient of MeCN in H₂O/NH₄HCO₃ (10 mM)+0.1% NH₄OH as mobile        phase; PrepMethod P: The compound was purified by preparative        HPLC on a XBRIDGE C18 ODB column (5 μm, 250×19 mm ID) using a        gradient of MeCN in H₂O/NH₄HCO₃ (10 mM)+0.1% NH₄OH as mobile        phase; PrepMethod Q: The compound was purified by preparative        HPLC on a WATERS SUNFIRE C18 column (5 μm, 150×30 mm ID) using a        gradient of MeCN in H₂O/FA (0.1 M) as mobile phase; PrepMethod        R: The compound was purified by preparative HPLC on a XBRIDGE        SHIELD RP18 OBD column (5 μm, 150×30 mm ID) using a gradient of        MeCN in H₂O/NH₄HCO₃ (10 mM) as mobile phase; PrepMethod S: The        compound was purified by preparative SFC on a Phenomenex Luna        Hilic column (5 μm, 250×30 mm ID) using a gradient of MeOH/NH₃        (20 mM) in CO₂ as mobile phase; PrepMethod T: The compound was        purified by preparative HPLC on a WATERS XSELECT CSH OBD column,        (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O/FA (0.1M)        as mobile phase; PrepMethod U: The compound was purified by        preparative SFC on a PHENOMENEX Luna Hilic column (5 μm, 250×30        mm ID) using a gradient of EtOH/FA (20 mM) in CO₂ as mobile        phase; PrepMethod V: The compound was purified by preparative        HPLC on a Waters Xselect CSH OBD column, (5 μm, 250×19 mm ID)        using a gradient of MeCN in H₂O/FA (0.1M) as mobile phase;        PrepMethod X: The compound was purified by preparative HPLC on a        XBridge™ C18 ODB column (5 μm, 250×30 mm ID) using a gradient of        MeCN in H₂O/NH₄HCO₃ (10 mM)+0.1% NH₄OH as mobile phase;        PrepMethod Y: The compound was purified by preparative HPLC on a        XBridge™ C18 ODB column (5 μm, 150×30 mm ID) using a gradient of        MeCN in H₂O/NH₄HCO₃ (10 mM)+0.1% NH₄OH as mobile phase;        PrepMethod Z: The compound was purified by preparative HPLC on a        XBridge™ C18 ODB column (5 μm, 150×30 mm ID) using a gradient of        MeCN in H₂O/AcOH (0.1%) as mobile phase. SFC Prep Methods:        PrepMethod SFC-A: The compound was purified by preparative SFC        on a Waters™ BEH, (5 μm, 250×30 mm ID) using MeOH/H₂O (NH₃ 50        mM) (97/3) in CO₂ as mobile phase;

In some instances the compound may be dissolved in a solvent e.g. DMSOand filtered through a syringe filter prior to purification onpreparative HPLC.

Relevant fractions were collected, combined and freeze-dried orevaporated to give the purified compound or relevant fractions werecollected, combined and concentrated at reduced pressure, extracted withDCM or EtOAc, and the organic phase was dried either over Na₂SO₄ or byusing a phase-separator, and then concentrated at reduced pressure togive the purified compound.

-   -   (ix) chiral preparative chromatography was carried out using        HPLC or SFC on a standard HPLC or SFC instruments, respectively,        and using either isocratic or gradient run with mobile phase as        described below;    -   (x) yields, where present, are not necessarily the maximum        attainable, and when necessary, reactions were repeated if a        larger amount of the reaction product was required;    -   (xi) where certain compounds were obtained as an acid-addition        salt, for example a mono-hydrochloride salt or a        di-hydrochloride salt, the stoichiometry of the salt was based        on the number and nature of the basic groups in the compound,        the exact stoichiometry of the salt was generally not        determined, for example by means of elemental analysis data;    -   (xii) in general, the structures of the end-products of the        Formula (I) were confirmed by nuclear magnetic resonance (NMR)        and/or mass spectral techniques; proton NMR chemical shift        values were measured on the delta scale using BRUKER AVANCE III        300, 400, 500 and 600 spectrometers, operating at ¹H frequencies        of 300, 400, 500 and 600 MHz, respectively. The experiments were        typically recorded at 25° C. Chemical shifts are given in parts        per million with the solvent as internal standard. Protons on        heteroatoms such as NH and OH protons are only reported when        detected in NMR and can therefore be missing. In certain        instances, protons can be masked or partially masked by solvent        peaks and will therefore either be missing and not reported or        reported as multiplets overlapping with solvent. The following        abbreviations have been used (and derivatives thereof, e.g. dd,        doublet of doublets, etc.): s, singlet; d, doublet; t, triplet;        q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. In        some cases, the structures of the end-products of the        Formula (I) might appear as rotamers in the NMR-spectrum, in        which instances only peaks of the major rotamer are reported. In        certain instances, the structures of the intermediates and/or        the end-products of the Formula (I) might appear as rotamers in        the NMR-spectrum, in which instances peaks of all rotamers are        reported, and only the total number of protons are reported. The        ratio of major vs minor rotamer is reported if known.        Electrospray mass spectral data were obtained using a WATERS        ACQUITY UPLC coupled to a WATERS single quadrupole mass        spectrometer or similar equipment, acquiring both positive and        negative ion data, and generally, only ions relating to the        parent structure are reported; high resolution electrospray mass        spectral data were obtained using a WATERS XEVO qToF mass        spectrometer or similar equipment, coupled to a WATERS ACQUITY        UPLC, acquiring either positive and negative ion data, and        generally, only ions relating to the parent structure are        reported;    -   (xiii) intermediates were not necessarily fully purified but        their structures and purity were assessed by TLC, analytical        HPLC/UPLC, analytical GCMS and/or NMR analysis and/or mass        spectrometry;    -   (xiv) unless stated otherwise compounds containing an asymmetric        carbon and/or sulfur atom were not resolved;    -   (xv) in general Examples and Intermediate compounds are named        using CHEMDRAW PROFESSIONAL version 20.1.1.125 from PerkinElmer.        CHEMDRAW PROFESSIONAL version 20.1.1.125 generates the names of        chemical structures using the Cahn-Ingold-Prelog (CIP) rules for        stereochemistry and follows IUPAC rules as closely as possible        when generating chemical names. Stereoisomers are differentiated        from each other by stereodescriptors cited in names and assigned        in accordance with the CIP rules. A “rac-” prefix indicates that        a compound is racemic.    -   (xvi) in addition to the ones mentioned above, the following        abbreviations and units have been used:    -   AcOH Acetic acid    -   Aq Aqueous    -   Boc tert-butyloxycarbonyl    -   t-BuOH tert-Butanol    -   Brine Saturated aqueous sodium chloride solution    -   Calcd Calculated    -   CBz Benzyloxycarbonyl    -   COMU        (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium        hexafluorophosphate (CAS Registry Number 1075198-30-9)    -   18-Crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane    -   DABAL-Me₃ CAS Registry Number 137203-34-0    -   DCM Dichloromethane    -   DEAD Diethyl azodicarboxylate    -   DIC Diisopropylmethanediimine    -   DIPEA N-ethyl-N-isopropyl-propan-2-amine    -   DMAP N,N-dimethylpyridin-4-amine    -   DMF N,N-dimethylformamide    -   DMSO Dimethyl sulfoxide    -   DPPA Diphenyl phosphorazidate    -   EDC 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine    -   ESI Electrospray ionization    -   Et₂O Diethyl ether    -   EtOAc Ethyl acetate    -   EtOH Ethanol    -   eq equivalents    -   FA Formic acid    -   (g) gas    -   GC gas chromatography    -   HPLC High performance liquid chromatography    -   HATU        (1-(Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxo        hexafluorophosphate    -   HOBt 1-hydroxybenzotriazole; hydrate    -   HRMS High resolution mass spectrometry    -   ID inner diameter    -   Lawesson's reagent        2,4-bis(4-Methoxyphenyl)-1,3,2,4-dithiadiphosphetane        2,4-disulfide    -   LiHMDS Lithium bis(trimethylsilyl)amide    -   LC Liquid chromatography    -   Me₃Al Trimethyl aluminum    -   MeCN Acetonitrile    -   Mel iodomethane    -   MeMgBr Methylmagnesium bromide    -   MeOH Methanol    -   MS Mass spectrometry    -   MTBE Methyl tert-butyl ether    -   m/z mass spectrometry peak(s)    -   NBS N-bromosuccinimide    -   NIS 1-Iodopyrrolidine-2,5-dione    -   NMR Nuclear magnetic resonance    -   PE petroleum ether    -   Pd-118        [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)    -   Pd—C Palladium on charcoal    -   PPh₃ Triphenylphosphane    -   sat Saturated    -   SFC Supercritical fluid chromatography    -   TBTU        2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium        tetrafluoroborate    -   TEA Triethylamine    -   TFA Trifluoroacetic acid    -   THF Tetrahydrofuran    -   TLC Thin layer chromatography    -   UPLC ultra performance liquid chromatography    -   UV ultraviolet    -   Xphos Pd G3        (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)        methanesulfonate

Intermediate 1: Ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate

EDC (43.5 g, 227.07 mmol) and HOBt (15.34 g, 113.53 mmol) were added toethyl (Z)-2-amino-2-(hydroxyimino)acetate (15 g, 113.53 mmol),2,4,5-trifluoro-3-hydroxybenzoic acid (21.81 g, 113.53 mmol) and NaHCO₃(28.6 g, 340.60 mmol) in DMF (150 mL) under a N₂(g) atmosphere. Theresulting solution was stirred at 100° C. for 1 h. The reaction mixturewas filtered through CELITE, and the filtrate was concentrated, dilutedwith DCM (300 mL) and washed with water (300 mL). The organic layer wasdried over Na₂SO₄, filtered and evaporated. The crude product waspurified by flash chromatography on a C18 column (gradient 50-60% MeCNin water (FA)) to give the title compound (7.0 g, 21%) as a white solid;MS (ESI) m/z [M+H]⁺ 289; ¹H NMR (300 MHz, DMSO-d₆) δ 1.36 (t, 3H), 4.45(m, 2H), 7.28-7.81 (m, 1H), 11.70 (s, 1H).

Alternative Synthesis of Intermediate 1: SOCl₂ (1.7 mol eq, 0.96 L) wasadded to a mixture of 2,4,5-trifluoro-3-hydroxybenzoic acid (1.45 kg,7.55 mol) and toluene (14.5 L) at 75-85° C. over 4 hours. Thetemperature was adjusted to 85-95° C., and the mixture stirred for 20 h.The mixture was concentrated to about 4 L at below 50° C. and thencharged with toluene (14.5 L). This process of concentration andcharging with toluene was repeated twice, before the resulting mixturewas charged with toluene (14.5 L) and concentrated to about 3 L at below50° C. to give a solution of 2,4,5-trifluoro-3-hydroxybenzoyl chloride.This was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate(966.4 g, 7.31 mol, 1.05 eq), pyridine (2629.9 g, 33.25 mol, 5 eq) andMeCN (5.6 L) at 20-30° C. The resulting mixture was stirred at 20-30° C.for 0.5-1.5 h before being heated to 55-65° C. The mixture was thenheated with a residence time of 45 minutes in flow at a temperature of140° C. (see FIG. 1 ). After heating, the reaction mixture was quenchedin flow with a mixture of EtOH (1.4 L) and water (1.4 L) pre-heated to atemperature of 20-30° C. At the end of the flow reaction, the resultingmixture was adjusted to pH 2-3 with 2M HCl (13.72 L) over 6 h at 5-15°C. EtOAc (14 L) was added and the mixture stirred for 2 h at 20-30° C.The organic was then separated and the aqueous extracted with EtOAc (14L). The combined organics were then concentrated under vacuum at 35-45°C. before being charged with EtOH (14 L). The process of concentrationand charging with EtOH was repeated and then the mixture wasconcentrated under vacuum at 35-45° C. The mixture was then treated withwater (12.6 L) over 2 hours at 20-30° C. and then stirred at 20-30° C.for 16 h. The resulting mixture was filtered and rinsed with water (2.8L) and n-heptane (4.2 L) and the resulting filter cake dried at 30-40°C. for 16 h to give the title compound as a solid (1.52 kg @95.28% w/w,1.45 Kg @ 100% w/w, 5.03 mol, 66.6% yield across the 2 stages).

Intermediate 2:5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic Acid

LiOH (0.482 g, 20.13 mmol) dissolved in water (10 ml) was added to ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (1.45 g, 5.03 mmol) in THF (10 ml) at 20° C. The solutionwas stirred for 2 h at rt and then at 60° C. for 1 h. The THF wasevaporated off and the water phase was cooled to 0° C., acidified with1M HCl, and then freeze dried overnight. The white solid was dissolvedin EtOAc and washed with a small amount of 1M HCl. The organic layer waspassed through a phase separator and concentrated to give the titlecompound (1.08 g, 83%) as a white beige solid; MS m/z (ESI) [M−H]⁻259.0; ¹H NMR (500 MHz, DMSO-d₆) δ 6.93-7.21 (1H, m), 10.60 (1H, s).

Intermediate 3:(R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanone

In a vial 5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acidIntermediate 23 (22 mg, 0.08 mmol), NaHCO₃ (20 mg, 0.24 mmol), HOBt (17mg, 0.09 mmol) and EDC (25 mg, 0.13 mmol) were dissolved in DMF (0.4 ml)and stirred for 5 min. Then a solution of (R)-3-phenylpyrrolidine HCl(14 mg, 0.08 mmol) in DMF (0.4 ml) was added and the reaction mixturewas stirred at rt over night. The reaction was quenched with sat NH₄Cl(aq, 2 ml) and the mixture was extracted with DCM (×3). The combinedorganic layers were washed with 1 M KHSO₄ and brine, passed through aphase separator and concentrated. The crude was purified by flashchromatography on silica (gradient: 10-50% EtOAc in heptane) to give thetitle compound (17 mg, 53%) as a white solid; MS (ESI) m/z [M+H]⁺ 418.1.

Intermediate 4: Ethyl(S)—N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butanoyl)glycinate

To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid(600 g, 3.0 mol) and ethyl benzylglycinate (600 g, 3.0 mol) in 5 L ofDCM was added TEA (597 g, 6.0 mol) and TBTU (1043 g, 3.3 mol). Thesolution was stirred at rt overnight, and then diluted with 10% HCl (1L). The organic layer was separated and washed with sat NaHCO₃ (1 L) andbrine (1 L), dried over MgSO₄. The DCM was removed under vacuum, and thecrude product was purified by column chromatography on silica (gradient:0-10% EtOAc in PE) to give the title compound (1005 g, 90%) as a yellowliquid; MS (ESI) m/z [M+Na]⁺ 401.1.

Intermediate 5: Ethyl(S)—N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butyl)glycinate

The reaction was carried out in three parallel reactions. To a solutionof ethyl(S)—N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butanoyl)glycinateIntermediate 4 (357 g, 0.94 mol) in 2 L of anhydrous THF was addeddropwise a solution of BH₃ (10 M, 240 ml) at 0° C. within 2 h and undera N₂(g) atmosphere. The reaction mixture was stirred at 35° C.overnight. The reaction was quenched with MeOH (100 ml) and water (500mL), and the mixture was extracted with DCM (3×500 mL). The organiclayer was combined, dried over MgSO₄, and evaporated under vacuum. Thecrude product was purified by column chromatography on silica (gradient:0-5% EtOAc in PE) to give the title compound (110 g, 32%) as a yellowliquid; MS (ESI) m/z [M+H]⁺ 365.1.

Intermediate 6: (S)-4-Benzyl-6-ethylpiperazin-2-one

To a solution of ethyl(S)—N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butyl)glycinateIntermediate 5 (300 g, 0.82 mol) dissolved in dry DCM (500 ml) was addeddropwise TFA (500 ml) at 0° C. The solution was stirred at 20° C. for 10h. The solvent was removed and sat Na₂CO₃ (500 ml) was added, and thesolution was stirred for another 10 h. The mixture was extracted withDCM (3×200 mL). The combined organic layers were dried over MgSO₄, andevaporated under vacuum to give the title compound (144 g, 80%) as apale yellow solid; MS (ESI) m/z [M+H]⁺ 218.9.

Intermediate 7: (S)-6-Ethylpiperazin-2-one

To a solution of (S)-4-benzyl-6-ethylpiperazin-2-one Intermediate 6 (87g, 0.4 mol) in MeOH was added Pd/C (17 g, 16 mmol). The mixture wasstirred at 50° C. under H₂(g) (50 psi) for 2 days. The mixture wasfiltered, and the filtrate was concentrated in vacuum to give the titlecompound (42 g, 82%) as a white solid; MS (ESI) m/z [M+H]⁺ 129.1.

Intermediate 8:4-(((2-Hydroxyethyl)amino)methyl)tetrahydro-2H-pyran-4-ol

A solution of 1,6-dioxaspiro[2.5]octane (100 g, 0.877 mol) and2-aminoethan-1-ol (64 g 1.05 mol) in dry EtOH (1 L) was stirred at 50°C. for 14 h. The mixture was concentrated in vacuum to give the titlecompound (110 g, 92%); MS (ESI) m/z [M+H]⁺ 176.

Intermediate 9: Benzyl(2-hydroxyethyl)(4-hydroxytetrahydro-2H-pyran-4-yl)methyl)carbamate

To crude 4-(((2-hydroxyethyl)amino)methyl)tetrahydro-2H-pyran-4-olIntermediate 8 (180 g, 1.02 mol) and TEA (203 g, 2.01 mol) in dry DCM (2L) was added benzyl carbonochloridate (183 g, 1.07 mol) dropwise at 0°C. After the addition, the reaction was stirred at 25° C. for 3 h. Thereaction mixture was concentrated and purified by flash chromatography(PE:EtOAc, 2:1) to give the title compound (280 g, 88%); MS (ESI) m/z[M+Na]⁺ 332.

Intermediate 10: Benzyl 1,9-dioxa-4-azaspiro[5.5]undecane-4-carboxylate

Crude benzyl(2-hydroxyethyl)((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)carbamateIntermediate 9 (140 g, 0.45 mol) and PPh₃ (140 g, 0.53 mol) weredissolved under a N₂(g) atmosphere in dry THF (1800 mL) and the mixturewas stirred at 25° C. A solution of DEAD (94 g, 0.53 mol) in dry THF(200 mL) was added dropwise and the reaction mixture was stirred at 25°C. for 12 h. The reaction mixture was concentrated and purified by flashcolumn chromatography (PE:EtOAc, 3:1) to give the title compound (100 g,76%); ¹H NMR (CDCl₃, 400 MHz) 7.29-7.33 (m, 5H); 5.11-5.12 (m, 2H);4.08-4.16 (m, 6H), 3.47 (br s, 2H); 3.33 (br s, 2H); 2.01-2.02 (d, 2H);1.71-1.74 (m, 2H).

Intermediate 11: 1,9-Dioxa-4-azaspiro[5.5]undecane

The benzyl 1,9-dioxa-4-azaspiro[5.5]undecane-4-carboxylate Intermediate10 (60 g, 210 mmol) and Pd/C (10 g) in THF (1 L) was stirred at 25° C.under H₂(g) (40 psi) for 12 h. The suspension was filtered and thefiltrates were concentrated to dryness to give crude product. EtOAc/HCl(100 mL) was added and the mixture was stirred at rt for 2 h. The solidswere filtered off and dried under vacuum to give the title compound(22.5 g, 58%) as a HCl salt; MS (ESI) m/z [M+H]⁺ 158.

Intermediate 12: tert-Butyl4-(2-((5-bromopyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate

5-Bromo-2-chloropyridine (8.36 g, 43.42 mmol), tert-butyl4-(2-hydroxyethyl)piperazine-1-carboxylate (10 g, 43.42 mmol), KOH (4.87g, 86.84 mmol) and 18-crown-6 (0.459 g, 1.74 mmol) were dissolved intoluene (150 mL) and heated at reflux for 4 h. The reaction mixture wascooled and 80% of the solvent was evaporated. The reaction was quenchedwith water (100 mL) and extracted with Et₂O (3×100 mL). The organiclayer was dried over MgSO₄, filtered and evaporated to afford a yellowliquid. The crude gum was triturated with Et₂O and then evaporated togive the title compound (16.45 g, 98%) as an off white solid; MS (ESI)m/z [M+H]⁺ 388.0.

Intermediate 13: 1-(2-((5-Bromopyridin-2-yl)oxy)ethyl)piperazine

tert-Butyl 4-(2-((5-bromopyridin-2-yl)oxy)ethyl)piperazine-1-carboxylateIntermediate 12 (16.6 g, 42.97 mmol) and 6.0 M HCl in propan-2-ol (91mL, 3.00 mol) were stirred over night at 25° C. to afford a white solid.Et₂O (50 ml) was added to the reaction mixture and the precipitate wascollected by filtration, washed with Et₂O and dried under vacuum to givethe title compound (15 g, 97%) as a white solid; MS (ESI) m/z [M+H]⁺287.9.

Intermediate 14: 2,4,5-Trifluoro-N,3-dimethoxy-N-methylbenzamide

To 2,4,5-trifluoro-3-methoxybenzoic acid (1 g, 4.85 mmol) and HATU(2.214 g, 5.82 mmol) in DMF (14 ml) was added DIPEA (2.54 mL, 14.55mmol) and N,O-dimethylhydroxylamine HCl (0.6 g, 6.15 mmol). Theresulting solution was stirred at rt overnight. The reaction mixture wasdiluted with EtOAc and washed with 1 M HCl (aq), 1 M NaHCO₃ (aq), waterand brine. The organic phase was separated using a phase separator thenconcentrated. The crude oil was purified by flash chromatography onsilica (gradient: 30-70% EtOAc in heptane) to give the title compound(1.03 g, 85%) as a light yellow oil; MS (ESI) m/z [M+H]⁺ 250.1.

Intermediate 15: 1-(2,4,5-Trifluoro-3-methoxyphenyl)ethan-1-one

MeMgBr in THF (3.4 M, 5.31 mL, 18.06 mmol) was added dropwise to2,4,5-trifluoro-N,3-dimethoxy-N-methylbenzamide Intermediate 14 (0.9 g,3.61 mmol) in THF (12 ml) at 0° C. and under a N₂(g) atmosphere. Thesolution was stirred at rt for 1 h. The reaction was quenched whenpoured into an ice cooled mixture of 1 M HCl (aq, 15 ml) and THF (10mL). The mixture was diluted with EtOAc. The layers were separated andthe water layer was extracted with EtOAc. The combined organic layer waswashed with brine, and evaporated to give the crude title compound(0.736 g, 100%) as a light yellow oil; ¹H NMR (500 MHz, CDCl₃) δ 2.63(3H, d), 4.07 (3H, t), 7.38-7.47 (1H, m).

Intermediate 16: Ethyl2,4-dioxo-4-(2,4,5-trifluoro-3-methoxyphenyl)butanoate

LiHMDS in toluene (1 M, 4 mL, 4.00 mmol) was added to1-(2,4,5-trifluoro-3-methoxyphenyl)ethan-1-one Intermediate 15 (0.736 g,3.61 mmol) in THF (10 ml) and cooled to −20° C. under a N₂(g)atmosphere. The mixture was stirred at −20° C. for 40 min. Diethyloxalate (0.5 mL, 3.68 mmol) was added and the solution was stirred at rtfor 40 min. The reaction was quenched by adding 1 M HCl (aq, 15 ml) andthen EtOAc. The phases were separated and the organic layer was washedwith water and then concentrated to give a yellow solid. The cruderesidue was purified by flash chromatography on silica (gradient: 30-50%EtOAc (containing 1% AcOH) in heptane) to give the title compound (0.924g, 84%) as a beige solid; MS (ESI) m/z [M+H]⁺ 305.0.

Intermediate 17: Ethyl5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazole-3-carboxylate

Ethyl 2,4-dioxo-4-(2,4,5-trifluoro-3-methoxyphenyl)butanoateIntermediate 16 (0.924 g, 3.04 mmol) was dissolved in EtOH (99%, 10 ml)and hydroxylamine HCl (0.488 g, 7.02 mmol) was added. The yellowsolution was stirred at 80° C. for 3 h. The reaction mixture was cooledto rt and diluted with EtOAc, and washed once with 1 M HCl (aq) and oncewith water. The phases were separated using a phase separator and theorganic phase was concentrated. The crude product was purified by flashchromatography on silica (gradient: 20-40% EtOAc in heptane) to give thetitle compound (0.585 g, 64%) as a white solid; MS (ESI) m/z [M+H]⁺302.0.

Intermediate 18:((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazol-3-yl)methanone

(2R,6S)-2,6-Dimethylmorpholine (0.102 g, 0.89 mmol) was dissolved in drytoluene (1 ml) and Me₃Al in toluene (2 M, 0.830 mL, 1.66 mmol) was addeddropwise at rt under N₂(g) atmosphere. The resulting clear solution wasstirred at rt for 45 min. The above solution was added dropwise at rt toa stirred solution of ethyl5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazole-3-carboxylate Intermediate17 (0.2 g, 0.66 mmol) in toluene (1.3 ml) under N₂(g) atmosphere. Thesolution was heated to 60° C. for 20 h. Tartaric acid (30%, aq, 5 ml)was added dropwise until 2 clear phases appeared. The mixture wasextracted with EtOAc. The phases were separated. The water phase wasextracted again with EtOAc. The organic phases were combined andconcentrated. The residue was purified by preparative HPLC, PrepMethod D(gradient: 15-65%) to give the title compound (143 mg, 58%) as an yellowoil that became a solid when standing; MS (ESI) m/z [M+H]⁺ 371.2.

Intermediate 19: Methyl2-(2-(4-fluoro-3-hydroxybenzoyl)hydrazineyl)-2-oxoacetate

Methyl 2-chloro-2-oxoacetate (5.60 mL, 60.8 mmol) was added dropwise to4-fluoro-3-hydroxybenzohydrazide, WO2009105214, (6.9 g, 40.55 mmol) in1,4-dioxane (200 ml) and THF (200 ml) at 5° C. and under a N₂(g)atmosphere. The resulting mixture was stirred at 25° C. for 0.5 h. Thesolvent was removed under reduced pressure to afford the title compound(10.20 g, 98%) as a white solid; MS (ESI) m/z [M+H]⁺ 257.

Intermediate 20: Methyl5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylate

A mixture of methyl2-(2-(4-fluoro-3-hydroxybenzoyl)hydrazineyl)-2-oxoacetate Intermediate19 (10 g, 39.03 mmol) in POCl₃ (150 ml) was stirred at 90° C. for 1 h.The solvent was removed under reduced pressure and water was added tothe residue. The precipitate was collected by filtration, washed withwater (20 ml) and dried under vacuum to afford the title compound (6.40g, 69%) as a light brown solid; MS (ESI) m/z [M+H]⁺ 239.

Intermediate 21: 1,2,4-Trifluoro-5-iodo-3-methoxybenzene

An oven-dried 20 mL microwave vial was charged with2,4,5-trifluoro-3-methoxybenzoic acid (0.5 g, 2.43 mmol), K₃PO₄ (0.515g, 2.43 mmol) and iodine (2.463 g, 9.70 mmol) and a stirring bar. Thevial was capped, evacuated and backfilled with N₂(g). Anhydrous MeCN (8ml) was added and the reaction mixture was heated at 120° C. for 23 h.The reaction mixture was allowed to reach rt and 15% Na₂SO₃ (aq) wasadded until the dark colour disappeared. A second batch was prepared asdescribed above and the reaction mixtures were combined and extractedwith DCM (×3). The combined organic layer was washed with 8% Na₂CO₃(aq), passed through a phase separator and concentrated. The residue waspurified by straight phase flash chromatography on silica (gradient:5-17% MTBE in pentane) to give the title compound (0.841 g, 60%) as anearly colourless oil; MS (EI) m/z [M]⁺ 288.0.

Intermediate 22 tert-Butyl5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylate

A 20 mL microwave vial was charged with1,2,4-trifluoro-5-iodo-3-methoxybenzene Intermediate 21 (407 mg, 1.41mmol), EtOH (12 ml), (5-(tert-butoxycarbonyl)thiophen-2-yl)boronic acid(322 mg, 1.41 mmol), Pd-118 (138 mg, 0.21 mmol), 2 M K₂CO₃ (aq) (2.12ml, 4.24 mmol) and a stirring bar. The vial was capped, evacuated andbackfilled with N₂(g) (×3) and then heated at 80° C. for 1.5 h. EtOAcand water was added and the mixture was washed with 8% NaHCO₃ (aq). Theaqueous layer was extracted with EtOAc and the combined organic layerswere passed through a phase separator and concentrated. The residue waspurified by straight phase flash chromatography on silica (gradient:0-30% EtOAc in heptane). Fractions containing the title compound werepooled and concentrated, and the residue was dissolved in MTBE (ca 10ml) and treated with SILIAMET S THIOL (1 g, loading: 1.4 mmol/g) at 40°C. for 30 min. The mixture was filtered and the solid was washed withMTBE. The combined filtrates were concentrated and the residue waspurified by preparative HPLC, PrepMethod J, (gradient: 50-100%) to givethe title compound (176 mg, 36%); ¹H NMR (500 MHz, CDCl₃) δ 1.59 (9H,s), 4.08 (3H, d), 7.13 (1H, ddd), 7.34 (1H, dd), 7.69 (1H, dd).

Intermediate 23:5-(2,4,5-Trifluoro-3-methoxyphenyl)thiophene-2-carboxylic Acid

TFA (0.5 mL) was added to a solution of tert-butyl5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylate Intermediate22 (167 mg, 0.48 mmol) in DCM (1 mL) and the solution was stirred at rtfor 1.5 h during which a precipitate formed. Volatiles were removed invacuo and the crude was further azeotroped with MeCN (×3) to give thetitle compound (137 mg, 98%) as an off-white solid; MS m/z (ESI) [M−H]⁻287.1.

Intermediate 24:((2R,6S)-2,6-Dimethylmorpholino(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanone

HATU (206 mg, 0.54 mmol) was added to a stirred solution of5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acidIntermediate 23 (130 mg, 0.45 mmol) and DIPEA (0.236 mL, 1.35 mmol) in amixture of MeCN (3 mL) and EtOAc (3 mL) and the resulting solution wasstirred at rt for 2-3 min. (2R,6S)-2,6-Dimethylmorpholine (0.074 mL,0.59 mmol) was added and the reaction mixture was stirred at rt for 30min. The reaction solution was diluted with EtOAc and washedsequentially with sat Na₂CO₃ (aq) and water. The organic layer waspassed through a phase separator and concentrated. The residue waspurified by preparative HPLC, PrepMethod J, (gradient: 40-85%). Thefractions containing the title compound were pooled and concentrated tonear dryness and then partitioned between DCM and water using a phaseseparator. The organic layer was concentrated to give the title compound(145 mg, 83%) as a solid; MS m/z (ESI) [M+H]⁺ 386.2.

Intermediate 25: tert-Butyl (1-cyclohexyl-1H-pyrazol-5-yl)carbamate

DPPA (2267 mg, 8.24 mmol) followed by TEA (2296 μl, 16.47 mmol) wereadded slowly to a stirred solution of1-cyclohexyl-1H-pyrazole-5-carboxylic acid (800 mg, 4.12 mmol) in t-BuOH(10 mL) at 15° C. The resulting solution was stirred at 80° C. for 16 hunder a N₂(g) atmosphere. The solvent was removed under reduced pressureand the residue was purified by reversed phase flash chromatography on aC18 column, (gradient: 6-59% MeCN in water) and then by preparativeHPLC, PrepMethod Q, (gradient: 48-60%) to afford the title compound(0.352 g, 32%) as a white solid; MS m/z (ESI) [M+H]⁺ 266.

Intermediate 26: tert-Butyl(1-cyclohexyl-1H-pyrazol-5-yl(methyl)carbamate

NaH (60%, 249 mg, 6.22 mmol) was added to tert-butyl(1-cyclohexyl-1H-pyrazol-5-yl)carbamate Intermediate 25 (330 mg, 1.24mmol) in DMF (4 mL) at 0° C. and the reaction mixture was stirred at rtfor 1 h. Mel (0.101 mL, 1.62 mmol) was added and the reaction mixturewas stirred at 25° C. for 1 h. The reaction was quenched by addition ofcooled 2 M NH₄Cl (aq, 30 mL, 60 mmol) at 10° C. The reaction mixture wasconcentrated and diluted with EtOAc (50 mL), and then washed with satNH₄Cl (3×50 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated to afford the title compound (0.340 g, 98%) as a yellowsolid; ¹H NMR (300 MHz, DMSO-d6) δ 1.11-1.45 (11H, m), 1.61-1.88 (7H,m), 3.05 (3H, s), 3.46-3.63 (1H, m), 3.72-3.84 (1H, m), 6.09 (1H, d),7.40 (1H, d).

Intermediate 27: 1-Cyclohexyl-N-methyl-1H-pyrazol-5-amine

4 M HCl in 1,4-dioxane (3 mL, 12 mmol) was added to tert-butyl(1-cyclohexyl-1H-pyrazol-5-yl)(methyl)carbamate Intermediate 26 (340 mg,1.22 mmol) in 1,4-dioxane (3 mL) at 25° C. The resulting solution wasstirred at 25° C. for 5 h. The solvent was removed under reducedpressure to afford the title compound (0.250 g, 95%) as a yellow oil; MSm/z (ESI) [M+H]⁺ 180.

Intermediate 28: tert-Butyl3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylate

tert-Butyl propiolate (373 mg, 2.96 mmol) was added to a mixture of4-fluoro-3-methoxybenzaldehyde oxime (200 mg, 1.18 mmol), KCl (88 mg,1.18 mmol) and OXONE (1090 mg, 1.77 mmol) in MeCN (2 ml) and H₂O (2 ml)cooled to 0° C. The temperature was allowed to reach rt and theresulting suspension was stirred at 10° C. for 15 h. The reactionmixture was filtered through CELITE. The process was repeated 17 timesusing a total of 21.4 mmol 4-fluoro-3-methoxybenzaldehyde oxime. Thecombined filtrates were concentrated under reduced pressure and theresidue was purified by reversed phase flash chromatography on a C18column, (gradient: 16-63% MeCN in H₂O) to afford the title compound(0.397 g, 6%) as a light brown solid; MS m/z (ESI) [M+H]⁺ 294.

Intermediate 29: 3-(4-Fluoro-3-methoxyphenyl)isoxazole-5-carboxylic Acid

TFA (5 ml, 64.90 mmol) was added to tert-butyl3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylate Intermediate 28 (390mg, 1.33 mmol) in DCM (10 ml) at 15° C. The resulting solution wasstirred at 15° C. for 2.5 h. The solvent was removed under reducedpressure to afford the title compound (0.325 g, 99%) as a beige solid;MS m/z (ESI) [M+H]⁺ 238.

Intermediate 30:N-(1-Cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-methoxyphenyl)-N-methylisoxazole-5-carboxamide

DIC (215 μl, 1.38 mmol) was added slowly to a stirred solution of3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylic acid Intermediate 29(170 mg, 0.69 mmol), TFA (170 mg, 0.69 mmol) and1-cyclohexyl-N-methyl-1H-pyrazol-5-amine Intermediate 27 (148 mg, 0.83mmol) in DMF (2 mL) at 15° C. The resulting solution was stirred at 80°C. for 16 h. The reaction mixture was diluted with water (20 mL), andextracted with EtOAc (3×50 mL). The organic layers were combined andwashed with sat brine (10×20 mL), dried over Na₂SO₄, filtered andevaporated. The residue was purified by preparative TLC (EtOAc:PE, 1:2)and then by reversed phase flash chromatography on a C18 column(gradient: 0-69% MeCN in water) to afford the title compound (0.109 g,40%) as a colourless oil which solidified on standing; MS m/z (ESI)[M+H]⁺ 399.

Intermediate 31:(3-(4-Fluoro-3-methoxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanone

DIPEA (255 μl, 1.46 mmol) was added to3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylic acid Intermediate 29(120 mg, 0.49 mmol), 3-phenylpyrrolidine (86 mg, 0.58 mmol) and HATU(370 mg, 0.97 mmol) in DMF (2.5 mL) at 15° C. The resulting solution wasstirred at 15° C. for 2 h. The reaction mixture was diluted with satNaHCO₃ (aq, 20 mL) and extracted with EtOAc (3×50 mL). The combinedorganic layers were washed sequentially with sat brine (5×20 mL) andwater (20 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated and the residue was purified by preparative TLC (EtOAc:PE,1:1), to afford the title compound (0.119 g, 67%) as a beige solid; MSm/z (ESI) [M+H]⁺ 367.

Intermediate 32: Ethyl 4-(4-fluoro-3-hydroxyphenyl)-2,4-dioxobutanoate

LiHMDS in THF (1M, 14.27 ml, 14.27 mmol) was added dropwise at −20° C.to 1-(4-fluoro-3-hydroxyphenyl)ethan-1-one (1.0 g, 6.49 mmol) in THF (15ml) and the reaction mixture was stirred at −20° C. for 1 h. Diethyloxalate (2.84 g, 19.46 mmol) was added and the reaction mixture wasstirred for 2 h at rt. The reaction was quenched by addition of 2 M HCl(10 mL). The reaction mixture was diluted with EtOAc (150 ml) and washedwith 2 M HCl (2×50 ml). The organic layer was dried over Na₂SO₄,filtered and evaporated to afford the title compound (1.50 g, 91%) as asolid; ¹H NMR (300 MHz, CDCl₃) δ 15.17 (s, 1H), 7.70 (dd, 1H), 7.58(ddd, 1H), 7.22 (dd, 1H), 7.04 (s, 1H), 5.56 (s, 1H), 4.43 (q, 2H), 1.44(t, 3H).

Intermediate 33: Ethyl5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate

A mixture of hydroxylamine HCl (274 mg, 3.94 mmol) and ethyl4-(4-fluoro-3-hydroxyphenyl)-2,4-dioxobutanoate Intermediate 32 (500 mg,1.97 mmol) in AcOH (20 ml) was stirred for 2 h at 100° C. The solventwas removed under reduced pressure and the residue was diluted withEtOAc (50 ml) and washed with sat NaHCO₃ (2×20 mL). The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue was washedwith Et₂O (50 ml) and dried to afford the title compound (0.150 g, 30%)as a light brown solid; MS m/z (ESI) [M+H]⁺ 252.

Intermediate 34: 5-(4-Fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic Acid

A solution of NaOH (191 mg, 4.78 mmol) in water (2 ml) was added toethyl 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate Intermediate33 (400 mg, 1.59 mmol) in EtOH (2 mL). The reaction mixture was stirredvigorously at 50° C. for 4 h. The pH of the reaction mixture wasadjusted to 2 using 0.1 M HCl. The solvent was removed under reducedpressure and the crude product was purified by reversed phase flashchromatography on a C18 column, (gradient: 0-40% MeCN in watercontaining 0.1% FA) to afford the title compound (0.280 g, 79%) as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.23-7.35 (m, 2H), 7.39(ddd, 1H), 7.48 (dd, 1H), 10.44 (s, 1H).

Intermediate 35: 3-Ethynyl-2,5,6-trifluorophenol

Dimethyl (1-diazo-2-oxopropyl)phosphonate (2.62 g, 13.63 mmol) was addedto 2,4,5-trifluoro-3-hydroxybenzaldehyde (1.6 g, 9.09 mmol) and K₂CO₃(3.77 g, 27.26 mmol) in MeOH (20 mL) at 20° C., and the resultingsolution was stirred at 20° C. for 4 h. The reaction mixture wasfiltered through CELITE and the filtrate was concentrated under reducedpressure. The residue was purified by preparative TLC (MeOH:DCM, 1:15),to afford the title compound (0.450 g, 29%) as a yellow oil; MS m/z(ESI) [M−H]⁻ 171.

Intermediate 36: Ethyl5-(2,4,5-Trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate

TEA (1215 μl, 8.72 mmol) was added to 3-ethynyl-2,5,6-trifluorophenolIntermediate 35 (300 mg, 1.74 mmol) and ethyl(Z)-2-chloro-2-(hydroxyimino)acetate (1.32 g, 8.72 mmol) in DCM (5 mL)at 20° C., and the resulting solution was stirred at 45° C. for 70 h.The reaction mixture was concentrated, diluted with EtOAc (25 mL) andwashed with water (25 mL). The organic layer was dried over Na₂SO₄,filtered and evaporated. The residue was purified by preparative TLC(MeOH:DCM, 1:15), to afford the title compound (0.300 g, 60%) as ayellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 1.13-1.30 (m, 3H), 4.23-4.40(m, 2H), 7.27 (d, 1H), 7.57 (m, 1H), 11.48 (s, 1H).

Intermediate 37:5-(2,4,5-Trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylic Acid

LiOH (117 mg, 4.87 mmol) was added to ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate Intermediate36 (280 mg, 0.97 mmol) in a mixture of EtOH (3 mL) and water (0.75 mL)at 20° C. The resulting solution was stirred at 20° C. for 3 h. Thereaction mixture was adjusted to pH 7 using 0.1 M HCl. The solvent wasremoved under reduced pressure to afford the title compound (0.250 g,99%) as a yellow solid; MS m/z (ESI) [M−H]⁻ 258.

Intermediate 38: Ethyl5-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1,2,4-oxadiazole-3-carboxylate

NaHCO₃ (1.908 g, 22.71 mmol) was added to2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-4-carboxylic acid (1.568g, 7.57 mmol), EDC (2.90 g, 15.14 mmol) and HOBt monohydrate (2.046 g,15.14 mmol) in DMF (30 mL) at 25° C. The mixture was stirred at 25° C.for 10 min. A solution of ethyl (Z)-2-amino-2-(hydroxyimino)acetate (1g, 7.6 mmol) in DMF (10 mL) was added and the resulting mixture wasstirred at 25° C. for 30 min and then at 80° C. for 3 h. The reactionmixture was diluted with EtOAc (75 mL) and washed with water (4×300 mL).The organic layer was dried over Na₂SO₄, filtered and evaporated. Theresidue was purified by reversed phase flash chromatography on a C18column, (gradient: 30-60% MeCN in water) to afford the title compound(0.940 g, 41%) as a white solid; MS m/z (ESI) [M+H]⁺ 304.

Intermediate 39: Ethyl5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate

EDC (2.90 g, 15.1 mmol) was added to ethyl(Z)-2-amino-2-(hydroxyimino)acetate (1.00 g, 7.57 mmol),4-fluoro-3-hydroxybenzoic acid (1772 mg, 11.35 mmol) and NaHCO₃ (1.91 g,22.7 mmol) in DMF (20 mL) and the resulting mixture was stirred at 100°C. for 2 h. The reaction mixture was diluted with EtOAc (750 mL) andextracted with EtOAc (3×250 ml). The combined organic layer was driedover Na₂SO₄, filtered and evaporated. The residue was purified bystraight phase flash chromatography on silica, (gradient 40-50% EtOAc inPE) to afford the title compound (1.200 g, 63%) as a white solid; MS m/z(ESI) [M+H]⁺ 253.

Intermediate 40:5-(4-Fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic Acid

A mixture of ethyl5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate Intermediate39 (470 mg, 1.86 mmol) and 2 M LiOH (aq, 9.32 mL, 18.6 mmol) in EtOH (10ml) was stirred at 60° C. for 1 h. The organic solvent was removed underreduced pressure and the reaction mixture was adjusted to pH 5-6 with 2M HCl. The mixture was diluted with H₂O (50 ml) and extracted with EtOAc(3×50 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated to afford the title compound (0.400 g, 96%); MS m/z (ESI)[M+H]⁺ 225.

Intermediate 41: 2-(4-Fluoro-3-hydroxyphenyl)oxazole-5-carboxylic Acid

Methyl 2-bromooxazole-5-carboxylate (470 mg, 2.28 mmol),(4-fluoro-3-hydroxyphenyl)boronic acid (391 mg, 2.51 mmol), K₃PO₄hydrate (1576 mg, 6.84 mmol) and XPhos Pd G3 (97 mg, 0.11 mmol) wereadded to a vial and the reaction mixture was flushed with N₂(g). THF (10ml) and water (10 ml) were added and the reaction mixture was flushedwith N₂(g) again. The reaction mixture was heated in a preheated heatingblock at 60° C. overnight. The reaction mixture was allowed to reach rt.Another batch was prepared as described above starting with methyl2-bromooxazole-5-carboxylate (50 mg, 0.24 mmol). The combined reactionmixtures were diluted with EtOAc and sat NH₄Cl (aq). The aqueous layerwas extracted with EtOAc (×3). The combined organic layers were driedover MgSO₄, filtered and concentrated under reduced pressure to give aresidue. The aqueous layer was then acidified to pH 1 using 2 M HCl, andextracted with EtOAc (×4), and the combined organic layers were driedover MgSO₄, filtered and concentrated under reduced pressure to give asecond residue. The residues were combined and purified by straightphase flash chromatography on silica (gradient: 0-10% MeOH in EtOAc).The product containing fractions were combined, concentrated anddissolved in EtOAc. The organic layer was extracted with 0.1 M NaOH(aq). The aqueous layer was acidified using 2 M HCl and extracted withEtOAc (×3). The combined organic layers were dried over MgSO₄, filteredand the solvent was removed under reduced pressure to afford the titlecompound (370 mg, 73%); MS m/z (ESI) [M+H]⁺ 224.

Intermediate 42: 3-(4-Fluoro-3-hydroxyphenyl)-3-oxopropanenitrile

MeCN (0.62 mL, 1.18 mmol) was added to a stirred suspension of NaH (60%in oil, 0.094 g, 2.35 mmol) in THF (1 mL), and the resulting mixture wasstirred at rt for 10 min. Methyl 4-fluoro-3-hydroxybenzoate (0.100 g,0.59 mmol) was added, and the resulting mixture was heated to 50° C. for70 h. H₂O was added, the mixture was acidified with 3.8 M HCl andextracted with EtOAc. The organic layer was concentrated, and theresidue was purified by straight phase flash chromatography on silica(gradient: 0-100% EtOAc in heptane) to give the title compound (0.075 g,71%) as a white solid; MS (ESI) m/z [M−H]⁻ 311.

Intermediate 43: Ethyl4-cyano-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate

TEA (0.117 mL, 0.84 mmol) was added to a stirred suspension of3-(4-fluoro-3-hydroxyphenyl)-3-oxopropanenitrile Intermediate 42 (0.075g, 0.42 mmol) in EtOH (99.5%, 1.5 mL), and the resulting mixture wasstirred at rt for 10 min. Ethyl (Z)-2-chloro-2-(hydroxyimino)acetate(0.063 g, 0.42 mmol) was added and the reaction mixture was stirred atrt for 18 h. The mixture was concentrated, and the residue was purifiedby straight phase flash chromatography on silica (gradient: 0-50% EtOAcin heptane) to give the title compound (0.056 g, 48%) as a white solid;MS (ESI) m/z [M−H]⁻ 275.

Intermediate 44: Ethyl4-cyano-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate

MeCN (1.53 mL, 29.1 mmol) was added to a stirred suspension of NaH (60%in oil, 2.33 g, 58.2 mmol) in THF (24 mL), and the resulting mixture wasstirred at rt for 15 min. Methyl 2,4,5-trifluoro-3-hydroxybenzoate (3.00g, 14.6 mmol) in THF (6 ml) was added dropwise, and the resultingmixture was heated to 50° C. for 20 h. H₂O (450 ml) was added, and themixture was washed with heptane, acidified with 3.8 M HCl and extractedwith EtOAc. The organic layer was concentrated, and the residue wassuspended in EtOH (99.5%, 75 mL). TEA (4.66 mL, 33.4 mmol) was added,and the resulting mixture was stirred at rt for 10 min. Ethyl(Z)-2-chloro-2-(hydroxyimino)acetate (2.53 g, 16.7 mmol) was added andthe mixture was stirred at rt for 18 h. The mixture was concentrated,and the residue was purified by straight phase flash chromatography onsilica (gradient: 8-13% EtOAc in heptane). The impure product wascombined with the crude product from another batch prepared as describedabove, starting with methyl 2,4,5-trifluoro-3-hydroxybenzoate (1.32 g,6.14 mmol), and the combined crude product was resolidified from DCM togive the title compound as a white solid (0.900 g, 12%); MS (ESI) m/z[M−H]⁻ 311; ¹H NMR (500 MHz, CD₃OD) δ 7.37 (ddd, 1H), 4.53 (q, 2H), 1.47(t, 3H).

Intermediate 45: N-Methyl-1-phenyl-1H-tetrazol-5-amine

A solution of 5-chloro-1-phenyl-1H-tetrazole (2 g, 11.07 mmol) inmethanamine (33% in EtOH, 2 mL) was stirred at 25° C. for 1 h. Thesolvent was removed under reduced pressure. The crude product waspurified by flash chromatography on silica (gradient: 0-60% EtOAc in PE)to give the title compound (1.2 g, 61%) as a white solid; MS (ESI) m/z[M+H]⁺=176.0

Intermediate 46: tert-Butyl(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)prolinate

DIPEA (771 μL, 4.41 mmol) was added slowly to5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acidIntermediate 23 (424 mg, 1.47 mmol), tert-butyl prolinate (252 mg, 1.47mmol) and HATU (1398 mg, 3.68 mmol) in DMF (10 mL) cooled to 10° C.under N₂ atmosphere. The resulting solution was stirred at 20° C. for 14h. The reaction mixture was diluted with EtOAc (50 mL) and washedsequentially with sat brine (1×100 mL), sat NaHCO₃ (1×100 mL) and water(1×100 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated. The residue was purified by preparative TLC (EtOAc:PE, 1:3)to give the title compound (0.255 g, 39%) as a pale yellow solid; MS(ESI) m/z [M+H]⁺=442.0

Intermediate 47:(5-(2,4,5-Trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)proline

A solution of HCl (4 M in dioxane, 60.8 μL, 2 mmol) in 1,4-dioxane (0.5mL) was added dropwise to a stirred solution of tert-butyl(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)prolinateIntermediate 46 (120 mg, 0.27 mmol) in 1,4-dioxane (0.5 mL) cooled to10° C. The resulting solution was stirred at 20° C. for 14 h. Thesolvent was removed under reduced pressure. The crude product waspurified by crystallisation from EtOAc to give the title compound (0.105g, 100%) as a white solid; MS (ESI) m/z [M+H]⁺=386.0

Intermediate 48:N,N-Dimethyl-1-(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide

EDC (80 mg, 0.42 mmol) and HOBt (56.1 mg, 0.42 mmol) were added to(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)prolineIntermediate 47 (80 mg, 0.21 mmol), dimethylamine HCl (16.93 mg, 0.21mmol) and DIPEA (109 μL, 0.62 mmol) in DMF (1 mL) at 20° C. under N₂atmosphere. The resulting solution was stirred at 20° C. for 2 h. Thereaction mixture was concentrated, diluted with EtOAc (20 mL) and washedsequentially with water (20 mL). The organic layer was dried overNa₂SO₄, filtered and evaporated. The residue was purified by preparativeTLC (MeOH:DCM, 1:10) to give the title compound (0.060 g, 70%) as awhite solid; MS (ESI) m/z [M+H]⁺=413

Intermediate 49: tert-Butyl(Z)-4-((((1-amino-2-methylpropylidene)amino)oxy)carbonyl)-3,6-dihydropyridine-1(2H)-carboxylate

TBTU (524 mg, 1.63 mmol) was added to a solution of1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid(309 mg, 1.36 mmol) and DIPEA (0.521 mL, 2.99 mmol) in DCM (6 ml) at rt.The mixture was stirred for ^(˜)10 min after which a solution/mixture of(Z)—N′-hydroxyisobutyrimidamide (176 mg, 1.72 mmol) in DCM (2 ml) wasadded. The reaction mixture was stirred for 3 h at rt and was thenwashed with 8% NaHCO₃ (aq, 3×5 ml) using a phase separator.

The organic layer was concentrated and the residue was purified by flashchromatography on silica (gradient: 0-75% EtOAc in heptane) to give thetitle compound (141 mg, 33%) as a white solid; MS (ESI) m/z [M+H]⁺=312.4

Intermediate 50: tert-Butyl4-(3-isopropyl-1,2,4-oxadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

A solution of sodium acetate (0.784 mL, 2.15 mmol) in water (0.784 ml)was added to a mixture of tert-butyl(Z)-4-((((1-amino-2-methylpropylidene)amino)oxy)carbonyl)-3,6-dihydropyridine-1(2H)-carboxylateIntermediate 49 (610 mg, 1.96 mmol) in EtOH (6 ml) and the mixture wasstirred at 86° C. for 5.5 h. The solvents were removed under reducedpressure and the residue was partitioned between DCM and water using aphase separator. The organic layer was concentrated under reducedpressure and the residue was purified by preparative HPLC, PrepMethod J(gradient: 40-80%) to give the title compound (339 mg, 59%); MS m/z(ESI) [M−tBu]⁺=238.2

Intermediate 51:3-Isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,4-oxadiazole

TFA (3 ml) was added to a solution of tert-butyl4-(3-isopropyl-1,2,4-oxadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylateIntermediate 50 (325 mg, 1.11 mmol) in DCM (3 ml) at rt and the solutionwas stirred at rt for 45 min. The solvents were removed under reducedpressure and the residue was dissolved in DCM and washed with 1 M NaOH(aq) and water. The organic layer was concentrated to give crude titlecompound (204 mg, 95%) as a light brown oil; MS (ESI) m/z [M+H]⁺=194.2

Intermediate 52: Methyl3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate

A mixture of 2,4,5-trifluoro-3-hydroxybenzonitrile (249 mg, 1.44 mmol),hydroxylammonium chloride (120 mg, 1.73 mmol) and NaHCO₃ (193 mg, 2.30mmol) in MeOH (2.5 ml) was stirred at 50° C. for 23 h. The reactionmixture was concentrated and the residue was suspended in pyridine andcooled to 0° C. Methyl 2-chloro-2-oxoacetate (0.199 mL, 2.16 mmol) wasadded and the mixture was stirred at rt for 20 min and then at 50° C.for 1.5 h. The reaction mixture was allowed to cool to rt and was pouredonto a mixture of ice and 4 M HCl (aq, 7 mL). The resulting mixture wasextracted with EtOAc and the organic layer was washed with water andbrine, passed through a phase-separator and concentrated. The residuewas purified by preparative HPLC, PrepMethod J, (gradient: 20-65%) togive the title compound (153 mg, 39%) as a white solid; MS m/z (ESI)[M−H]⁻ 273.0.

Intermediate 53: Ethyl5-(3,4-difluoro-5-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate

Oxalyl dichloride (4.09 mL, 47.7 mmol) and a catalytic amount of DMF(0.154 mL, 1.99 mmol) were added to a stirred suspension of3,4-difluoro-5-hydroxybenzoic acid (3.46 g, 19.9 mmol) in DCM (50 ml) atrt, and the resulting mixture was stirred at rt for 20 h. The reactionmixture was concentrated and co-evaporated twice from toluene. Theresidue was dissolved in in THF (20 ml) and added dropwise to a stirredsolution of ethyl (Z)-2-amino-2-(hydroxyimino)acetate (2.63 g, 19.9mmol) in pyridine (40 mL, 494 mmol) at rt. The resulting mixture washeated to 70° C. for 5 days, cooled to rt and poured out on a stirredmixture (400 ml) of 3.8 M HCl (150 ml) and ice. The mixture was stirredat rt for 1 h. The solid was filtered off and washed with H₂O to yieldthe crude product as a brown solid. The crude product was dissolved inDCM (^(˜)50 ml) and loaded on a plug of silica (14 g). The product waseluted with DCM (40 ml) and heptane/EtOAc (1:1, 100 mL). The impureproduct was combined with the crude product from another batch preparedas described above, starting with 3,4-difluoro-5-hydroxybenzoic acid(1.00 g, 5.74 mmol), and the combined crude product was resolidifiedfrom DCM to give the title compound (1.75 g, 25%) as an off-white solid;MS (ESI) m/z [M−H]⁻ 269.

Intermediate 54: 2,4,5-Trifluoro-3-methoxybenzothioamide

Lawesson's reagent (1.774 g, 4.39 mmol) was added to a solution of2,4,5-trifluoro-3-methoxybenzamide (1.5 g, 7.31 mmol) in THF (30 ml) andthe reaction mixture was heated at 50° C. for 50 min. The reactionmixture was concentrated and the residue was purified by straight phaseflash chromatography on silica (0-20% EtOAc in heptane) to give thetitle compound (1.225 g, 76%) as a yellow solid; MS m/z (ESI) [M−H]⁻220.1.

Intermediate 55: Ethyl2-(2,4,5-trifluoro-3-methoxyphenyl)thiazole-5-carboxylate

A solution of 2,4,5-trifluoro-3-methoxybenzothioamide Intermediate 54(1.095 g, 4.95 mmol) and ethyl 2-chloro-3-oxopropanoate (0.820 g, 5.45mmol) in toluene (25 ml) was heated at 105-110° C. for 4 h. The reactionmixture was concentrated under reduced pressure and the residue waspurified by straight phase flash chromatography on silica, (0-30% EtOAcin heptane) to give an orange solid which was further purified bytrituration with heptane to give the title compound (282 mg, 18%) as apale orange solid; MS m/z (ESI) [M+H]⁺ 318.1.

Intermediate 56:((2R,6S)-2,6-Dimethylmorpholino)₂-(2,4,5-trifluoro-3-methoxyphenyl)thiazol-5-yl)methanone

Me₃Al (2 M in toluene) (0.989 ml, 1.98 mmol) was added dropwise to asolution of (2R,6S)-2,6-dimethylmorpholine (0.140 mL, 1.11 mmol) inanhydrous toluene (1.1 mL) under an atmosphere of N₂(g) at rt. Thereaction mixture was stirred at rt for 1 h and was then added dropwiseat rt to a stirred slurry of ethyl2-(2,4,5-trifluoro-3-methoxyphenyl)thiazole-5-carboxylate Intermediate55 (251 mg, 0.79 mmol) in toluene (1.6 mL) under an atmosphere of N₂(g).The resulting solution was heated at 60° C. for 9 h and then cooled to0° C. Tartaric acid (30%, aq, 10 mL) was added dropwise and then themixture was extracted with EtOAc×2). The combined organic layer waswashed with water, dried over Na₂SO₄, filtered and concentrated underreduced pressure. DCM was added to the residue and the resulting mixturewas filtered. The filtrate was concentrated to give the title compound(288 mg, 94%); MS m/z (ESI) [M+H]⁺ 387.2.

Example 1:(R)-(5-(4-Fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(3-phenylpyrrolidin-1-yl)methanone

DIPEA (0.440 mL, 2.52 mmol) was added dropwise to methyl5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylate Intermediate20 (100 mg, 0.42 mmol) and (R)-3-phenylpyrrolidine, HCl (463 mg, 2.52mmol) in DMF (4 mL) at 25° C. and under a N₂(g) atmosphere, and thereaction mixture was stirred at 80° C. for 16 h. The reaction wasquenched with water (100 mL), extracted with EtOAc (3×100 mL), and theorganic layer was dried over Na₂SO₄, filtered and evaporated. The crudeproduct was purified by preparative HPLC, PrepMethod E, (gradient:42-52%) to afford the title compound (61 mg, 41%) as a white solid; HRMS(ESI) m/z [M+H]⁺ calcd for C₁₉H₁₇FN₃O₃: 354.1248, found: 354.1254; ¹HNMR (300 MHz, DMSO-d₆) δ 1.97-2.18 (1H, m), 2.22-2.45 (overlapping withsolvent, m), 3.41-3.72 (overlapping with solvent, m), 3.72-4.15 (2H, m),4.17-4.56 (1H, m), 7.13-7.56 (7H, m), 7.59-7.72 (1H, m), 10.64 (1H, s).

Example 2:(3-Phenoxyazetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

COMU (1.08 g, 2.51 mmol) was added to5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (436 mg, 1.68 mmol), DIPEA (2.93 mL, 16.8 mmol) and3-phenoxyazetidine (250 mg, 1.68 mmol) in DMF (2.5 mL) under a N₂(g)atmosphere. The resulting mixture was stirred at 25° C. for 3 h. Brine(75 mL) was added and the mixture was extracted with EtOAc (3×50 mL).The combined organic layers was dried over Na₂SO₄, filtered andevaporated. The residue was purified by reversed phase flashchromatography on a C18 column (gradient: 40-60% MeCN in water) toafford the title compound (0.089 g, 14%) as a yellow solid; HRMS (ESI)m/z [M+H]⁺ calcd for C₁₈H₁₃F₃O₄: 392.0852, found: 392.0840; ¹H NMR (400MHz, DMSO-d₆) δ 11.71 (s, 1H), 7.68 (ddd, 1H), 7.38-7.28 (m, 2H),7.05-6.96 (m, 1H), 6.93-6.85 (m, 2H), 5.15 (ddd, 1H), 5.00 (ddd, 1H),4.62 (ddd, 1H), 4.47 (ddd, 1H), 4.08 (ddd, 1H).

Example 3:((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone

BBr₃ in DCM (1M, 1.06 mL, 1.06 mmol) was added dropwise to a solution of((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanoneIntermediate 24 (136 mg, 0.35 mmol) in DCM (5 mL) at 0° C. The reactionmixture was stirred for 1.5 h at rt. The reaction mixture was dilutedwith DCM and water was carefully added. The layers were separated andthe aqueous layer was acidified with 1M KHSO₄ and extracted with EtOAc(×2). The combined organic layers were passed through a phase separatorand concentrated. The residue was purified by preparative HPLC,PrepMethod J, (gradient: 30-70%) to give the title compound (110 mg,84%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₁₇H₁₇F₃NO₃S:372.0876, found: 372.0892; ¹H NMR (500 MHz, DMSO-d₆) δ 1.11 (6H, d),2.66 (overlapping with solvent, bs), 3.33 (1H, s), 3.52-3.62 (2H, m),4.16 (2H, s), 7.44 (1H, ddd), 7.48 (1H, dd), 7.59 (1H, d), 11.17 (1H,s).

Example 4:(3-(2-Methoxyphenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(2-Methoxyphenyl)pyrrolidine HCl (0.102 g, 0.48 mmol) was suspended inEtOAc and washed with 10% Na₂CO₃. The organic layer was concentrated,toluene (1 ml) and Me₃Al in toluene (2M, 0.599 mL, 1.20 mmol) was addedto the residue under a N₂(g) atmosphere and the resulting mixture wasstirred at rt for 1 h. The mixture was added to a stirred slurry ofethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (0.138 g, 0.48 mmol) in toluene (1.5 mL), and theresulting mixture was heated to 60° C. for 22 h. The mixture was cooledto rt, tartaric acid (30%, aq, 5 ml) was added and the mixture wasextracted with EtOAc (5 mL). The organic layer was concentrated and theresidue purified by reversed phase HPLC, PrepMethod C, (gradient20-80%), to afford the title compound (120 mg, 60%) as a colorlesssyrup; HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₁₇F₃N₃O₄: 420.1166, found:420.1164; ¹H NMR (500 MHz, CDCl₃) 2.15-2.28 (1H, m), 2.30-2.40 (1H, m),3.64-3.94 (6H, m), 4.00-4.1 (1H, m), 4.21-4.31 (1H, m), 6.89 (1H, ddd),6.94 (1H, tdd), 7.19 (1H, dd), 7.22-7.31 (1H, m), 7.37 (1H, m).

Example 5:N-(1-Cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-5-carboxamide

BBr₃ in DCM (1M, 10 mL, 10.00 mmol) was added slowly to a stirredsolution ofN-(1-cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-methoxyphenyl)-N-methylisoxazole-5-carboxamideIntermediate 30 (90 mg, 0.23 mmol) in anhydrous DCM (2 ml) cooled to 0°C. and under a N₂(g) atmosphere. The resulting solution was stirred at15° C. for 2 h. Additional BBr₃ in DCM (1M, 20 mL, 20.00 mmol) was addedslowly to the solution above, cooled to 0° C., and under a N₂(g)atmosphere. The resulting solution was stirred at 15° C. for 2 h. Thereaction mixture was poured into 2 M NaOH (aq, 50 ml) and extracted withEtOAc (3×75 mL). The organic layers were combined, dried over Na₂SO₄,filtered and evaporated. The residue was purified by preparative TLC(EtOAc:PE, 1:2) and then further purified by preparative HPLC,PrepMethod N, (gradient: 45-55%) to afford the title compound (0.014 g,16%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₂FN₄O₃:385.1670, found: 385.1674; ¹H NMR (300 MHz, DMSO-d₆) δ 1.06-1.92 (10H,m), 3.31 (3H, s), 3.92-4.1 (1H, m), 6.30 (1H, d), 6.69 (1H, s),7.12-7.36 (3H, m), 7.51 (1H, d), 10.38 (1H, s).

Example 6:(3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-y)₃-phenylpyrrolidin-1-yl)methanone

BBr₃ in DCM (1M, 5 mL, 5 mmol) was added slowly to a stirred solution of(3-(4-fluoro-3-methoxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanoneIntermediate 31 (110 mg, 0.30 mmol) in anhydrous DCM (4 ml) cooled to 0°C. over a period of 5 min and under a N₂(g) atmosphere. The resultingsolution was stirred at 15° C. for 3 h under a N₂(g) atmosphere. Thereaction mixture was poured into sat NaHCO₃ (aq, 20 mL), cooled to 0°C., and extracted with EtOAc (4×50 mL). The organic layers werecombined, dried over Na₂SO₄, filtered and evaporated. The residue waspurified by preparative HPLC, PrepMethod N, (gradient: 46-56%) to affordthe title compound (0.050 g, 47%) as a white solid; HRMS (ESI) m/z[M+H]⁺ calcd for C₂₀H₁₈FN₂O₃: 353.1296, found: 353.1304; ¹H NMR (300MHz, DMSO-d₆) δ 1.94-2.2 (m, 1H), 2.24-2.42 (1H, m), 3.41-4.29 (5H, m),7.2-7.47 (7H, m), 7.51-7.61 (2H, m), 10.27 (1H, s).

Example 7:N-(1-Cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-3-carboxamide

(COCl)₂ (50.8 mg, 0.40 mmol) was added slowly to a mixture of5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid Intermediate 34(100 mg, 0.45 mmol) and DMF (1 μl, 0.01 mmol) in DCM (5 mL), cooled to5° C. and under a N₂(g) atmosphere. The resulting solution was stirredat 28° C. for 0.5 h. 1-Cyclohexyl-N-methyl-1H-pyrazol-5-amineIntermediate 27 (80 mg, 0.45 mmol) and TEA (836 μl, 6 mmol) were addedat 20° C. The resulting solution was stirred at 28° C. for 45 h. Water(20 ml) was added and the mixture was extracted with EtOAc (3×20 mL).The combined organic layers were dried over MgSO₄, filtered andevaporated. The residue was purified by reversed phase HPLC, PrepMethodO, (gradient: 28-61%) to afford the title compound (1.1 mg, 1%) as awhite solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₂FN₄O₃: 385.1670,found: 385.1680; ¹H NMR (400 MHz, DMSO-d6) δ 1.14-1.48 (6H, m),1.61-1.86 (7H, m), 3.30 (overlapping with solvent, s), 6.17 (1H, d),7.00 (1H, s), 7.23-7.34 (3H, m), 7.37 (1H, s).

Example 8:(R)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone

EDC (118 mg, 0.62 mmol), DMAP (7.54 mg, 0.06 mmol) and HOBt (83 mg, 0.62mmol) were added to5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acidIntermediate 37 (80 mg, 0.31 mmol), (R)-3-(4-chlorophenyl)pyrrolidine(56 mg, 0.31 mmol) and DIPEA (162 μl, 0.93 mmol) in DMF (2 ml) at 20° C.The resulting solution was stirred at 60° C. for 2 h under a N₂(g)atmosphere. The reaction mixture was concentrated, diluted with EtOAc(25 ml) and washed with water (25 mL). The organic layer was dried overNa₂SO₄, filtered and evaporated. The residue was purified by preparativeTLC (MeOH:DCM, 1:10) and further purified by preparative HPLC,PrepMethod P, (gradient 60-85%) to afford the title compound (0.025 g,19%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₁₅ClF₃N₂O₃:423.0718, found: 423.0718; ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ 2.01 (m,1H), 2.23-2.36 (m, 1H), 3.45-4.25 (m, 5H), 6.96-7.08 (m, 2H), 7.27-7.39(m, 4H).

Example 9:4-(3-(3-Phenylpyrrolidine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one

Me₃Al in toluene (2M, 0.5 mL, 1.00 mmol) was added to a solution of3-phenylpyrrolidine (73 mg, 0.49 mmol) in toluene (0.5 ml) at 25° C.stirred for 40 min. The resulting solution was added to a suspension ofethyl5-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1,2,4-oxadiazole-3-carboxylateIntermediate 38 (100 mg, 0.33 mmol) in toluene (0.5 ml) and under aN₂(g) atmosphere, and the mixture was stirred at 60° C. for 3 h. Thereaction mixture was diluted with water (75 ml) and filtered through apad of CELITE. The aqueous layer was extracted with EtOAc (3×20 mL). Theorganic layer was dried over Na₂SO₄, filtered and evaporated. Theresidue was purified by preparative HPLC, PrepMethod Q, (gradient:50-62%) to afford the title compound (34 mg, 25%) as a white solid; HRMS(ESI) m/z [M+H]⁺ calcd for C₁₉H₁₆F₃N₄O₃: 405.1168, found: 405.1166; ¹HNMR (300 MHz, DMSO-d₆) δ 2.00-2.18 (1H, m), 2.22-2.38 (1H, m), 3.42-4.18(m, 5H), 7.20-7.40 (5H, m), 7.57 (1H, d), 7.83 (1H, d), 12.65 (1H, s).

Example 10:4-(3-(4-(3-Methoxyphenyl)piperazine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one

DABAL-Me₃ (127 mg, 0.49 mmol) was added portionwise to1-(3-methoxyphenyl)piperazine HCl (95 mg, 0.42 mmol) in THF (1 mL). Theresulting mixture was stirred at 80° C. for 2 h under a N₂(g)atmosphere. A solution of ethyl5-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1,2,4-oxadiazole-3-carboxylateIntermediate 38 (100 mg, 0.33 mmol) in THF (1 ml) was added portionwiseto the mixture at 50° C. under a N₂(g) atmosphere. The resultingsolution was stirred at 80° C. for 2 h. The solvent was removed underreduced pressure. The residue was diluted with DMSO and filtered througha syringe filter. The filtrate was collected and purified by preparativeHPLC, PrepMethod Q, (gradient 33-63%) to afford the title compound (72mg, 48%) as a yellow solid; HRMS (ESI) m/z [M+H]+calcd for C₂₀H₁₉F₃N₅O₄:450.1384, found: 450.1380; ¹H NMR (300 MHz, DMSO-d₆) δ 2.94-3.11 (4H,m), 3.62-3.71 (2H, m), 3.79 (3H, s), 3.81-3.89 (2H, m), 6.83-7.06 (4H,m), 7.58 (1H, s), 7.85 (1H, s), 12.60 (1H, s).

Example 11:(R)-(5-(4-Fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone

(R)-3-Phenylpyrrolidine HCl (295 mg, 1.61 mmol),5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 40 (300 mg, 1.34 mmol), HOBt hydrate (246 mg, 1.61 mmol)and EDC (385 mg, 2.01 mmol) were suspended in DMF (8 ml) under a N₂(g)atmosphere. The resulting mixture was stirred at rt for 2 h and thenpurified by reversed phase flash chromatography on a C18 column(gradient: 40-50% MeCN in water (0.1% NH₄HCO₃)) to afford the titlecompound (0.188 g, 40%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcdfor C₁₉H₁₇FN₃O₃: 354.1248, found: 354.1256; ¹H NMR (400 MHz, CD₃OD) δ2.10-2.24 (1H, m), 2.36-2.48 (1H, m), 3.49-3.78 (2H, m), 3.79-4.39 (3H,m), 7.23-7.32 (2H, m), 7.32-7.38 (4H, m), 7.64-7.70 (1H, m), 7.71-7.78(1H, m).

Example 12:N-(1-Cyclohexyl-1H-pyrazol-5-yl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide

2-(4-Fluoro-3-hydroxyphenyl)oxazole-5-carboxylic acid Intermediate 41(70 mg, 0.31 mmol), 1-cyclohexyl-1H-pyrazol-5-amine (52 mg, 0.31 mmol)and HATU (131 mg, 0.35 mmol) was dissolved in DMF (2.95 mL).2,6-Dimethylpyridine (183 μl, 1.57 mmol) was added and the reactionmixture was stirred at rt overnight. The reaction mixture was dilutedwith EtOAc (20 mL), washed with sat NaHCO₃ (10 mL), and brine (3×10 mL).The organic layer was dried over MgSO₄, filtered and the solvent wasremoved under reduced pressure. The residue was purified by reversedphase HPLC, PrepMethod S, (gradient: 20-25%) to afford the titlecompound (0.012 g, 10%); HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₀FN₄O₃:371.1514, found: 371.1516; ¹H NMR (600 MHz, DMSO-d₆) δ 1.13-1.22 (1H,m), 1.27-1.38 (2H, m), 1.59-1.66 (1H, m), 1.73-1.88 (6H, m), 4-4.09 (1H,m), 6.18 (1H, d), 7.38 (1H, dd), 7.47 (1H, d), 7.62 (1H, s), 7.74 (1H,dd), 8.07 (1H, s), 10.40 (2H, s).

Example 13:5-(4-Fluoro-3-hydroxyphenyl)-3-(3-phenylpyrrolidine-1-carbonyl)isoxazole-4-carbonitrile

Me₃Al in toluene (2M, 0.185 mL, 0.37 mmol) was added to a stirredsolution of 3-phenylpyrrolidine (0.054 g, 0.37 mmol) in toluene (0.3 ml)under a N₂(g) atmosphere and the resulting mixture was stirred at rt for1 h. The mixture was added to ethyl4-cyano-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate Intermediate43 (0.034 g, 0.12 mmol), and the resulting mixture was heated to 60° C.for 22 h, and then cooled to rt. Tartaric acid (30%, aq, 2 ml) wasadded, and the mixture was extracted with EtOAc (5 mL). The organiclayer was concentrated, and the residue was purified by straight phaseflash chromatography on silica (gradient: 0-100% EtOAc in heptane) togive the title compound as a white solid (22 mg, 47%); HRMS (ESI) m/z[M+H]⁺; calcd for C₂₁H₁₇FN₃O₃: 378.1248, found: 378.1248; Mixture ofrotamers, ratio major:minor 1.2:1: ¹H NMR (500 MHz, DMSO-d₆) δ 2.08 (p),2.26-2.39 (m), 3.42-3.56 (m), 3.56-3.7 (m), 3.75-3.9 (m), 4-4.13 (m),4.27 (dd), 7.19-7.29 (m), 7.29-7.4 (m), 7.44-7.6 (m), 7.66 (ddd), 10.78(s)., total no of protons in spectrum: 16.

Examples 14 to 29 below were prepared from ethyl4-cyano-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylateIntermediate 44 in analogy to Example 13 using appropriate commerciallyavailable amines. HCl- and AcOH-salts of the amines were dissolved inMeOH, passed through a 5 g ISOLUTE NH₂ ion exchange column andconcentrated prior to use. The crude products were purified by thespecified method.

Example 14:3-(4-(3-(4-Fluorophenoxy)propyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (24mg, 37%); HRMS (ESI) m/z [M+H]⁺; calcd for C₂₄H₂₁F₄N₄O₄: 505.1494,found: 505.1486; ¹H NMR (500 MHz, CD₃OD) δ 2.04 (p, 2H), 2.7-2.82 (m,6H), 3.81-3.92 (m, 4H), 4.04 (t, 2H), 6.86-6.93 (m, 2H), 6.95-7.03 (m,2H), 7.31 (ddd, 1H).

Example 15:3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (9mg, 16%); HRMS (ESI) m/z [M+H]⁺; calcd for C₂₀H₁₅F₃N₅O₃: 430.1122,found: 430.1126; ¹H NMR (500 MHz, CD₃OD) δ 3.68 (dt, 4H), 3.93 (q, 4H),6.73 (dd, 1H), 6.89 (d, 1H), 7.35 (ddd, 1H), 7.61 (ddd, 1H), 8.09-8.17(m, 1H).

Example 16:3-(4-(3-Methoxyphenyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (25mg, 43%); HRMS (ESI) m/z [M+H]⁺; calcd for C₂₂H₁₈F₃N₄O₄: 459.1274,found: 459.1258; ¹H NMR (500 MHz, CD₃OD) δ 3.27 (dt, 4H), 3.76 (s, 3H),3.89-3.99 (m, 4H), 6.46 (dd, 1H), 6.53 (t, 1H), 6.59 (dd, 1H), 7.15 (t,1H), 7.35 (ddd, 1H).

Example 17:5-(2,4,5-Trifluoro-3-hydroxyphenyl)-3-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carbonyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (20mg, 29%); HRMS (ESI) m/z [M+H]⁺; calcd for C₂₁H₁₃F₆N₈O₃: 539.1008,found: 539.1016; ¹H NMR (500 MHz, CD₃OD) δ 3.85 (dt, 4H), 4.01 (dt, 4H),7.36 (ddd, 1H), 7.56 (d, 1H), 8.11 (d, 1H).

Example 18:3-(5-Fluoroisoindoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (12mg, 27%); HRMS (ESI) m/z [M+H]⁺; calcd for C₁₉H₁₀F₄N₃O₃: 404.0652,found: 404.0638; Mixture of rotamers, ratio major:minor 1:1: ¹H NMR (500MHz, CD₃OD) δ 5.00 (d), 5.26 (d), 7.04-7.14 (m), 7.17 (d), 7.31-7.45(m), total no of protons in spectrum: 8.

Example 19:N-(tert-Butyl)-4-cyano-N-(pyridin-2-ylmethyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxamide

The crude product was purified by preparative HPLC, PrepMethod A,(gradient: 5-95%) to give the title compound (2 mg, 4%); HRMS (ESI) m/z[M+H]⁺; calcd for C₂₁H₁₈F₃N₄O₃: 431.1326, found: 431.1334; ¹H NMR (600MHz, DMSO-d₆) δ 1.39 (s, 9H), 4.85 (s, 2H), 7.29 (m, 2H), 7.38 (d, 1H),7.78 (td, 1H), 8.54 (d, 1H), 11.88 (s, 1H).

Example 20:3-(3-Cyclopropyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod U, togive the title compound (12 mg, 23%); HRMS (ESI) m/z [M+H]⁺; calcd forC₂₁H₁₇F₃N₅O₃: 444.1278, found: 444.1276; Mixture of rotamers: ratiomajor:minor 2:1: ¹H NMR (600 MHz, DMSO-d₆) δ 0.64-0.68 (m), 0.7-0.73(m), 0.73-0.77 (m), 0.81-0.85 (m), 1.66 (tt), 1.79 (tt), 2.79 (q), 3.91(t), 3.98 (t), 4.68 (s), 4.72 (s), 7.48-7.56 (m), 11.86 (s), total no ofprotons in spectrum: 13.

Example 21:(S)-3-(3-(4-Chlorophenyl)pyrrolidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (18mg, 36%); HRMS (ESI) m/z [M+H]⁺; calcd for C₂H₁₄ClF₃N₃O₃: 448.0670,found: 448.0682; Mixture of rotamers: ratio major:minor: 1:1: ¹H NMR(500 MHz, DMSO-d₆) δ 2.06 (p), 2.26-2.39 (m), 3.42-3.55 (m), 3.56-3.68(m), 3.75-3.88 (m), 3.99-4.12 (m), 4.26 (dd), 7.33-7.44 (m), 7.45-7.56(m), 11.81 (s). total no of protons in spectrum: 13.

Example 22:3-((2R,6S)-2,6-Dimethylmorpholine-4-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (5mg, 9%); HRMS (ESI) m/z [M+H]⁺; calcd for C₁₇H₁₅F₃N₃O₄: 382.1008, found:382.1008; ¹H NMR (500 MHz, CD₃OD) δ 1.16 (d, 3H), 1.25 (d, 3H),2.61-2.71 (m, 1H), 2.98 (dd, 1H), 3.6-3.75 (m, 2H), 4.13 (dt, 1H), 4.50(dt, 1H), 7.34 (ddd, 1H).

Example 23:3-(4-(Benzo[d]oxazol-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (23mg, 38%); HRMS (ESI) m/z [M+H]⁺; calcd for C₂₂H₁₅F₃N₅O₄: 470.1070,found: 470.1048; ¹H NMR (500 MHz, CD₃OD) δ 3.84 (dt, 4H), 4.00 (q, 4H),7.08 (td, 1H), 7.19 (td, 1H), 7.29-7.4 (m, 3H).

Example 24:3-(4-(4-(4-Fluorophenyl)-2-oxo-2,3-dihydro-H-imidazol-1-yl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (5mg, 7%); HRMS (ESI) m/z [M+H]⁺; calcd for C₂₅H₁₈F₄N₅O₄: 528.1290, found:528.1276; ¹H NMR (500 MHz, CD₃OD) δ 1.9-2.16 (m, 4H), 3.10 (td, 1H),3.38-3.49 (m, 1H), 4.3-4.46 (m, 2H), 4.80-4.87 (m, 1H, obscured bysolvent OH), 6.97 (s, 1H), 7.04-7.14 (m, 2H), 7.29-7.38 (m, 1H),7.46-7.53 (m, 2H).

Example 25:3-(4-((5-Methoxypyridin-2-yl)oxy)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (32mg, 53%); HRMS (ESI) m/z [M+H]⁺; calcd for C₂₂H₁₈F₃N₄O₅: 475.1224,found: 475.1216; ¹H NMR (500 MHz, CD₃OD) δ 1.82-1.94 (m, 2H), 2.06-2.16(m, 2H), 3.73 (ddd, 1H), 3.77-3.87 (m, 4H), 3.96 (ddd, 1H), 4.02 (ddd,1H), 5.19-5.27 (m, 1H), 6.76 (d, 1H), 7.29-7.39 (m, 2H), 7.77 (d, 1H).

Example 26:3-(4-Hydroxy-4-(trifluoromethyl)piperidine-1-carbonyl)-1-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (9mg, 16%); HRMS (ESI) m/z [M+H]⁺; calcd for C₁₇H₁₈N₃O₄: 436.0726, found:436.0732; ¹H NMR (500 MHz, CD₃OD) δ 1.79-1.93 (m, 4H), 3.24 (td, 1H),3.56 (td, 1H), 4.15-4.25 (m, 1H), 4.59-4.7 (m, 1H), 7.32 (ddd, 1H).

Example 27:3-(3-Cyclopropyl-3-fluoroazetidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (10mg, 23%); HRMS (ESI) m/z [M+H]⁺; calcd for C₁₇H₁₂F₄N₃O₃: 382.0810,found: 382.0816; ¹H NMR (500 MHz, CD₃OD) δ 0.49-0.58 (m, 2H), 0.63-0.73(m, 2H), 1.44 (dddd, 1H), 4.14-4.28 (m, 2H), 4.5-4.66 (m, 2H), 7.33(ddd, 1H).

Example 28:5-(2,4,5-Trifluoro-3-hydroxyphenyl)-3-(3-(trifluoromethyl)azetidine-1-carbonyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod U, togive the title compound as an off-white solid (10 mg, 24%); HRMS (ESI)m/z [M+H]⁺; calcd for C₁₅H₈F₆N₃O₃: 392.0464, found: 392.0450; ¹H NMR(500 MHz, CD₃OD) δ ¹H NMR δ 3.65 (m, 1H), 4.21-4.26 (m, 1H), 4.41-4.48(m, 1H), 4.59-4.66 (m, 1H), 4.77-4.83 (m, 1H), 7.15 (ddd, 1H).

Example 29:3-(7-Cyano-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

The crude product was purified by preparative HPLC, PrepMethod C,(gradient: 20-80%) to give the title compound as an off-white solid (17mg, 34%); HRMS (ESI) m/z [M+H]⁺; calcd for C₂₁H₁₂F₃N₄O₃: 425.0856,found: 425.0828; Mixture of rotamers, ratio major:minor 1.5:1: ¹H NMR(500 MHz, CD₃OD) δ 3.10 (t), 4.04 (td), 4.97 (s), 5.04 (s), 7.35 (dddd),7.40 (dd), 7.53 (s), 7.56 (dd), 7.66 (s), total no of protons inspectrum: 10.

Example 30:2-(5-(2-Bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile

A mixture of2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrileExample 66 (0.006 g, 0.01 mmol) and NBS (5 mg, 0.03 mmol) in AcOH (0.5ml) was stirred at 80° C. for 1 h. The mixture was concentrated, and theresidue was purified by preparative HPLC, PrepMethod C, (gradient:20-80%) to give the title compound as a white solid (3 mg, 42%); HRMS(ESI) m/z [M+H]⁺ calcd for C₁₉H₁₁BrF₃N₄O₃: 478.9960, found: 478.9970;Mixture of rotamers, ratio major:minor 2:1: ¹H NMR (500 MHz, DMSO-d₆) δ3.09 (q), 3.87 (t), 4.01 (t), 4.85 (s), 4.93 (s), 7.40 (t), 7.46 (t),7.50 (d), 7.67 (d), 7.75 (dd), 12.08 (s), total no of protons inspectrum: 10.

Example 31:2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile

5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (38 mg, 0.15 mmol), HATU (111 mg, 0.29 mmol) and DMF (0.5ml) were mixed in a vial. 1,2,3,4-Tetrahydroisoquinoline-6-carbonitrileHCl (28 mg, 0.15 mmol) dissolved in DMF (0.5 ml) was added followed byDIPEA (153 μL, 0.88 mmol). The resulting yellow solution was stirred atrt over night. The reaction mixture was diluted with DMSO and purifiedby preparative HPLC, PrepMethod A, (gradient: 5-95%) to give the titlecompound (15 mg, 26%); HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₁₂F₃N₄O₃:401.0856, found: 401.0834; Mixture of rotamers ratio major:minor: 1:0.6:¹H NMR (600 MHz, DMSO-d₆) δ 2.97 (2H, dt), 3.79 (1.2H, t), 3.92 (0.8H,t), 4.84 (0.8H, s), 4.94 (1.2H, s), 7.52 (0.6H, d), 7.31 (0.4H, d)7.62-7.75 (3H, m), 11.71 (1H, s). Total no of protons in spectrum: 11.

Example 32:(2,2,6,6-Tetramethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (40 mg, 0.15 mmol), HATU (70 mg, 0.18 mmol) and DMF (1ml) were mixed in a vial. DIPEA (0.081 ml, 0.46 mmol) was added followedby 2,2,6,6-tetramethylmorpholine (33 mg, 0.23 mmol). The resultingyellow solution was stirred at rt for 2 h. The reaction mixture wasdiluted with DMSO and purified by preparative HPLC, PrepMethod B,(gradient: 5-95%) to give the title compound (17 mg, 29%); HRMS (ESI)m/z [M+H]⁺ calcd for C₁₇H₁₉F₃N₃O₄: 386.1322, found: 386.1324; ¹H NMR(600 MHz, DMSO-d₆) δ 1.09 (6H, s), 1.17 (6H, s), 3.32 (2H, s), 3.49 (2H,s), 6.99-7.12 (1H, m).

Example 33:(R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone

BBr₃ in DCM (1M, 122 μL, 0.12 mmol) was added dropwise to a solution of(R)-(3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanoneIntermediate 3 (17 mg, 0.04 mmol) in DCM (0.8 ml) at 0° C. The reactionwas stirred for 2.5 h at rt. The yellow reaction mixture was dilutedwith DCM and water was carefully added. The organic phase was separated.1 M KHSO₄ was added to the water phase, and it was extracted with EtOAc(×3). The combined organic layers were dried using a phase separator andconcentrated to give a white solid. The residue was purified bypreparative HPLC, PrepMethod C, (gradient: 25-65%) to give the titlecompound (12 mg, 73%); HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₁₇F₃NO₂S:404.0926, found: 404.0924; Mixture of rotamers: ¹H NMR (500 MHz,DMSO-d₆) δ 1.95-2.21 (1H, m), 2.23-2.44 (1H, m), 3.42-3.64 (2H, m,overlapping with water peak), 3.77 (11H, t), 3.84-4.08 (11H, in), 4.23(11H, t), 7.21-7.3 (11H, in), 7.3-7.49 (5H, in), 7.54-7.73 (21H, in),11.17 (11H, bs), total no of protons in spectrum: 16.

General Preparation A

The appropriate amine (0.08 mmol, 2 eq) was added to a solution of5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylicacidIntermediate 2 in DMF (0.08-0.2 M, 0.04 mmol, 1 eq) and HATU in DMF(0.15-0.4 M, 0.08 mmol, 2 eq). DIPEA (0.23 mmol, 6 eq) was added and thereaction was shaken at rt for 20 h. The solvent was removed underreduced pressure and the crude product was dissolved in DMSO (0.3 m,filtered and purified by preparative HPLC, using one of the followingmethods; PrepMethod F, G, H or I (gradient 2-94%).

TABLE 1 Examples 34-76 were prepared as described in General PreparationA using the appropriate amine described in the table below. The aminesare commercially available if not otherwise stated. Ex- am- ple HRMS(ESI) Purification No Structure Name m/z [M + H]⁺ Method 34

(S)-6-Ethyl-4-(5- (2,4,5-trifluoro- 3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl) piperazin-2-one calcd for C₁₅H₁₄F₃N₄O₄: 371.0962,found: 371.0952 F 35

(3-Isopropylmorpholino)(5- (2,4,5-trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₆H₁₇F₃N₃O₄: 372.1166, found:372.1154 F 36

((3R,5S)-3,5- Dimethylmorpholino) (5-(2,4,5- trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₁₅H₁₅F₃N₃O₄: 358.1008, found:358.1004 G 37

((3R,5S)-3,5- Dimethylpiperidin-1- yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)- 1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₆H₁₇F₃N₃O₃:356.1216, found: 356.1202 G 38

((2R,5S)-2,5- Dimethylpyrrolidin- 1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)- 1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₅H₁₅F₃N₃O₃:342.1060, found: 342.1030 F 39

Morpholino(5- (2,4,5-trifluoro-3- hydroxyphenyl)- 1,2,4-oxadiazol-3-yl)methanone calcd for C₁₃H₁₁F₃N₃O₄: 330.0696, found: 330.0674 G 40

Thiomorpholino (5-(2,4,5- trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazol-3- yl)methanone calcd for C₁₃H₁₁F₃N₃O₃S: 346.0468, found:346.0456 G 41

(Hexahydrocyclopenta [b][1,4] oxazin-4(4aH)-yl) (5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₁₆H₁₅F₃N₃O₄:370.1008, found: 370.0992 F 42

3-(4-(5-(2,4,5-Trifluoro-3- hydroxyphenyl)-1,2,4- oxadiazole-3-carbonyl)piperazin- 2-yl)benzonitrile calcd for C₂₀H₁₅F₃N₅O₃: 430.1122, found:430.1122 H 43

(8,8-difluoro-3- azabicyclo[3.2.1] octan-3-yl)(5- (2,4,5-trifluoro-3-hydroxyphenyl)- 1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₆H₁₃F₅N₃O₃:390.0872, found: 390.0848 F 44

Piperidin-1-yl(5- (2,4,5-trifluoro- 3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone calcd for C₁₄H₁₃F₃N₃O₃: 328.0904, found:328.0896 F 45

(6-Oxa-9-azaspiro [4.5]decan-9- yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)- 1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₇H₁₇F₃N₃O₄:384.1166, found: 384.1180 F 46

(S)-(5-(2,4,5-Trifluoro-3- hydroxyphenyl)- 1,2,4-oxadiazol-3-yl)(2-(trifluoromethyl) morpholino)methanone calcd for C₁₄H₁₀F₆N₃O₄:398.0570, found: 398.0558 F 47

(2-Isobutylmorpholino) (5-(2,4,5-trifluoro- 3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone calcd for C₁₇H₁₉F₃N₃O₄: found: 386.1284 F 48

(3,3- Dimethylmorpholino) (5-(2,4,5-trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₅H₁₅F₃N₃O₄: 358.1008, found:358.0990 F 49

(R)-(2- (Fluoromethyl) morpholino)(5-(2,4,5- trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol- 3-yl)methanone calcd for C₁₄H₁₂F₄N₃O₄:362.0758, found: 362.0742 F 50

((2R,5R)-2,5- Dimethylmorpholino) (5-(2,4,5- trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₁₅H₁₅F₃N₃O₄: 358.1008, found:358.0982 F 51

(R)-(7-Methyl- 1,4-oxazepan-4- yl)(5-(2,4,5-trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₅H₁₅F₃N₃O₄: 358.1008, found:358.0994 F 52

(5-Oxa-8-azaspiro [3.5]nonan-8- yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₁₆H₁₅F₃N₃O₄:370.1008, found: 370.1006 F 53

(1,9-Dioxa-4- azaspiro[5.5]undecan- 4-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₁₇H₁₇F₃N₃O₅:400.1114, found: 400.1104 F 54

((2S,6S)-2,6- Dimethylmorpholino) (5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₁₅H₁₅F₃N₃O₄:358.1008, found: 358.1012 G 55

(4-(4-Methoxyphenyl) piperazin- 1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₂₀H₁₈F₃N₄O₄:435.1274, found: 435.1276 I 56

4-(1-(5-(2,4,5-Trifluoro-3- hydroxyphenyl)-1,2,4- oxadiazole-3-carbonyl)piperidin- 4-yl)benzonitrile calcd for C₂₁H₁₆F₃N₄O₃: 429.1168,found: 429.1172 G 57

(4-(3-(4- Fluorophenoxy) propyl)piperazin- 1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)- 1,2,4-oxadiazol- 3-yl)methanone calcd for C₂₂H₂₁F₄N₄O₄:481.1494, found: 481.1500 G 58

(4-(Pyridin-2-yl) piperazin-1-yl)(5- (2,4,5-trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₈H₁₅F₃N₅O₃: 406.1122, found:406.1126 G 59

4-(1-(5-(2,4,5-Trifluoro-3- hydroxyphenyl)-1,2,4- oxadiazole-3-carbonyl)azetidin- 3-yl)benzonitrile calcd for C₁₉H₁₂F₃N₄O₃: 401.0856,found: 401.0858 I 60

(3-Phenylazetidin-1- yl)(5-(2,4,5- trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone calcd for C₁₈H₁₃F₃N₃O₃: 376.0904, found:376.0906 G 61

(4-(3-Methoxyphenyl) piperazin-1-yl)(5- (2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl) methanone calcd for C₂₀H₁₈F₃N₄O₄:found: 435.1276 I 62

(4-Phenyl-3,6- dihydropyridin- 1(2H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl) methanone calcd for C₂₀H₁₅F₃N₃O₃:402.1060, found: 402.1060 G 63

N-(3-Cyanophenyl)- N-methyl-5- (2,4,5-trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide MS m/z (ESI) [M − H]⁻ 373.1 G 64

(3,4- Dihydroisoquinolin-2(1H)- yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl) methanone calcd for C₁₈H₁₃F₃N₃O₃:376.0904, found: 376.0904 G 65

(5-Fluoroisoindolin-2-yl)(5- (2,4,5-trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₇H₁₀F₄N₃O₃: 380.0652, found:380.0654 I 66

2-(5-(2,4,5-Trifluoro-3- hydroxyphenyl)-1,2,4- oxadiazole-3-carbonyl)-1,2,3,4- tetrahydroisoquinoline-5- carbonitrile calcd for C₁₉H₁₂F₃N₄O₃:401.0856, found: 401.0862 I 67

(4-(3-Chloro-5-(2-methyl-2H- tetrazol-5-yl)pyridin-2-yl)piperazin-1-yl)(5-(2,4,5- trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone calcd for C₂₀H₁₆ClF₃N₉O₃: 522.1012, found:522.1020 I 68

(4-((5-Methoxypyridin-2- yl)oxy)piperidin-1-yl)(5- (2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₂₀H₁₈F₃N₄O₅:451.1224, found: 451.1230 G 69

(4-(2-((5-Bromopyridin-2- yl)oxy)ethyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3- hydroxyphenyl)- 1,2,4-oxadiazol-3-yl)methanone calcd for C₂₀H₁₈BrF₃N₅O₄: 528.0488, found: 528.0490 H 70

(4-(Pyridin-3-yloxy) piperidin-1-yl)(5- (2,4,5-trifluoro-3-hydroxyphenyl)- 1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₉H₁₆F₃N₄O₄:421.1118, found: 421.1122 H 71

N-((5,6-Dimethyl-1H- benzo[d]imidazol-2-yl) methyl)-N-methyl-5-(2,4,5-trifluoro-3- hydroxyphenyl)-1,2,4- oxadiazole-3-carboxamide calcdfor C₂₀H₁₇F₃N₅O₃: 432.1278, found: 432.1280 I 72

(4-(Benzo[d]oxazol-2- yl)piperazin-1-yl)(5-(2,4,5- trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₂₀H₁₅F₃N₅O₄:446.1070, found: 446.1076 H 73

N-Methyl-N-((5-methyl- 1H-benzo[d]imidazol- 2-yl)methyl)-5-(2,4,5-trifluoro-3- hydroxyphenyl)-1,2,4- oxadiazole-3-carboxamide calcdfor C₁₉H₁₅F₃N₅O₃: 418.1122, found: 418.1124 I 74

(3-(4-Fluorophenyl)azetidin- 1-yl)(5-(2,4,5- trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₈H₁₂F₄N₃O₃: 394.0810, found:394.0810 I 75

N-Isopropyl-N- ((3-methylpyridin- 2-yl)methyl)-5- (2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazole-3-carboxamide calcd for C19H18F3N4O3:407.1326, found: 407.1330 G 76

(3-Propylpyrrolidin-1-yl)(5- (2,4,5-trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazol- 3-yl)methanone calcd for C₁₆H₁₇F₃N₃O₃: 356.1216, found:356.1214 I

General Preparation B

5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylicacidIntermediate 2 in DMF (0.4 M, 0.06 mmol, 1 eq) followed by DIPEA (0.35mmol, 6 eq) and HATU in DMF (0.47 M, 0.12 mmol, 2 eq) were added to avial containing the appropriate amine (0.12 mmol, 2 eq). The reactionmixture was shaken at rt over night. The reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in DMSO(0.3 ml) and purified by preparative HPLC, using one of the followingmethods; PrepMethod F, G, H or I (gradient 2-94%).

TABLE 2 Examples 77-84 were synthesized and purified as described inGeneral Preparation B using the appropriate amines either as the freebase or as the corresponding HCl salt. The amine is commerciallyavailable if not otherwise stated. Example HRMS (ESI) Purification NoStructure Name m/z [M + H]⁺ Method 77

(1-Phenyl-3- azabicyclo[3.1.0]hexan-3- yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₂₀H₁₅F₃N₃O₃:402.1060, found: 402.1062 G 78

N-(1-(4- Methoxyphenyl)ethyl)-N- methyl-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazole-3-carboxamide calcd for C₁₉H₁₇F₃N₃O₄:408.1166, found: 408.1162 H 79

(3-(4- Fluorophenoxy)pyrrolidin-1- yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₁₉H₁₄F₄N₃O₄:424.0914, found: 424.0920 G 80

4-Phenyl-1-(5-(2,4,5- trifluoro-3-hydroxyphenyl)- 1,2,4-oxadiazole-3-carbonyl)piperidine-4- carbonitrile calcd for C₂₁H₁₆F₃N₄O₃: 429.1168,found: 429.1166 G 81

(4-Phenylpiperazin-1-yl)(5- (2,4,5-trifluoro-3- hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone calcd for C₁₉H₁₆F₃N₄O₃: 405.1168, found:405.1170 G 82

2-(4-(5-(2,4,5-Trifluoro-3- hydroxyphenyl)-1,2,4- oxadiazole-3-carbonyl)piperazin-1- yl)benzonitrile calcd for C₂₀H₁₅F₃N₅O₃: 430.1122,found: 430.1124 G 83

4-(4-(5-(2,4,5-Trifluoro-3- hydroxyphenyl)-1,2,4- oxadiazole-3-carbonyl)piperazin-1- yl)benzonitrile calcd for C₂₀H₁₅F₃N₅O₃: 430.1122,found: 430.1124 H 84

(4-(2- Methoxyphenyl)piperazin-1-yl) (5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4- oxadiazol-3-yl)methanone calcd for C₂₀H₁₈F₃N₄O₄:435.1274, found: 435.1276 G

Example 85:3-(1-(S-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)azetidin-3-yl)benzonitrile

5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (93 mg, 0.36 mmol), HATU (272 mg, 0.72 mmol) and DMF (3ml) were mixed in a vial. 3-(Azetidin-3-yl)benzonitrile HCl (80 mg, 0.41mmol) was added followed by DIPEA (375 μL, 2.15 mmol). The resultingsolution was stirred at rt over night. The reaction mixture was filteredand purified by preparative HPLC, PrepMethod D (gradient 20-60%). Thepure fractions were combined and the MeCN was evaporated. The remainingwater phase was extracted with EtOAc (×2). The combined organic layerwas concentrated to give a yellow oil that was purified by preparativeHPLC, PrepMethod D (gradient 30-80%). The relevant fractions werecombined and evaporated. The residue was dissolved in MeCN and purifiedby preparative HPLC, PrepMethod J (gradient 15-55%). The pure fractionswere combined and evaporated by freeze drying over night. The residuewas dissolved in EtOAc and washed with 1 M KHSO₄. The water phase wasextracted with EtOAc (×2). The organic layers were combined andevaporated. The residue was dissolved in MeCN/water and freeze driedover night to give the title compound (8.4 mg, 6%) as a white solid;HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₁₂F₃N₄O₃: 401.0856, found: 401.0846;¹H NMR (500 MHz, DMSO-d₆) 7.97-8.02 (1H, m), 7.73-7.82 (2H, m), 7.58(1H, t), 7.38 (1H, s), 4.94 (1H, t), 4.49-4.62 (2H, m), 4.03-4.21 (2H,m).

Example 86:2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile

5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (80 mg, 0.31 mmol), HATU (234 mg, 0.62 mmol) and DMF (1ml) were mixed in a vial. 1,2,3,4-Tetrahydroisoquinoline-7-carbonitrile(54 mg, 0.34 mmol) was added followed by DIPEA (322 μL, 1.85 mmol). Theresulting yellow solution was stirred at rt for 4 h. The reactionmixture was filtered and purified by preparative HPLC, PrepMethod D(gradient 15-55%). The pure fractions were combined and the MeCN wasevaporated. The remaining water phase was extracted with EtOAc (×2). Thecombined organic layers were concentrated to give a beige oil. The oilwas dissolved in MeCN and water was added. The compound was freeze driedover night to give a solid. Water was added to give a slurry that wassonicated for 5 min. The slurry was freeze dried over night to give thetitle compound (76 mg, 62%) as a beige solid; HRMS (ESI) m/z [M+H]⁺calcd for C₁₉H₁₂F₃N₄O₃: 401.0856, found: 401.0838; Mixture of rotamers:ratio major:minor: 1:0.6; ¹H NMR (500 MHz, DMSO-d₆) δ 3.01 (2H, dt),3.79 (1.2H, t), 3.93 (0.8H, t), 4.79 (0.8H, s), 4.90 (1.2H, s), 7.4-7.49(1H, m), 7.5-7.64 (1H, m), 7.64-7.71 (1H, m), 7.84 (1H, s), 11.81 (1H,bs). Total no of protons in spectrum: 11.

Example 87:((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(2R,6S)-2,6-Dimethylmorpholine (0.520 g, 4.51 mmol) was suspended in drytoluene (12 ml) and Me₃Al in toluene (2 M, 4.34 mL, 8.68 mmol) was addedunder a N₂(g) atmosphere, and the resulting mixture was stirred at rtfor 1 h. The above mixture was added to a stirred slurry of ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (1 g, 3.47 mmol) in toluene (12 mL). The resultingsolution was heated to 60° C. for 20 h. The mixture was cooled to rt,tartaric acid (30%, aq, 100 ml) was added and the mixture was extractedwith EtOAc. The organic layer was concentrated, and the residue waspurified by preparative HPLC, PrepMethod D (gradient 20-80%) to give thetitle compound (1.01 g, 81%) as a white solid; HRMS (ESI) m/z [M+H]⁺calcd for C₁₅H₁₅F₃N₃O₄: 358.1008, found: 358.0978; ¹H NMR (500 MHz,CD₃OD) δ 1.14 (3H, d), 1.25 (3H, d), 2.65 (1H, dd), 2.96 (1H, dd),3.57-3.79 (2H, m), 3.98 (1H, dt), 4.52 (1H, dt), 7.43-7.67 (1H, m).

Example 88:((2R,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

The title compound was prepared analogous to Example 87 from(2R,6R)-2,6-dimethylmorpholine and ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1. The crude product was purified by preparative HPLC,PrepMethod D (gradient 20-80%) to give the title compound (59 mg, 48%);HRMS (ESI) m/z [M+H]⁺ calcd for C₁₅H₁₅F₃N₃O₄: 358.1008, found: 358.1008;¹H NMR (500 MHz, CD₃OD) δ 1.20 (3H, d), 1.26 (3H, d), 3.43 (1H, dd),3.52 (1H, dd), 3.76 (1H, dd), 3.88 (1H, dd), 4.02-4.1 (1H, m), 4.1-4.18(1H, m), 7.46-7.64 (1H, m).

Example 89:((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone

The title compound was prepared analogous to Example 33 from((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazol-3-yl)methanoneIntermediate 18, but using 6 eq of BBr₃ in DCM (1 M). The crude productwas purified by preparative HPLC, PrepMethod D (gradient 15-55%) to givethe title compound (74 mg, 57%); HRMS (ESI) m/z [M+H]⁺ calcd forC₁₆H₁₆F₃N₂O₄: 357.1056, found: 357.1066; ¹H NMR (500 MHz, DMSO-d₆) δ1.05 (3H, d), 1.16 (3H, d), 2.55 (1H, dd, overlapping with water peak),2.88 (1H, dd), 3.52-3.62 (2H, m), 3.90 (1H, dt), 4.38 (1H, td), 7.14(1H, d), 7.48-7.57 (1H, m), 11.47 (1H, s).

The following compounds, Example 90-111, were also made by methodsanalogous to those described hereinbefore.

Example 90:(5-(4-Fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(5-oxa-8-azaspiro[3.5]nonan-8-yl)methanone

A solution of methyl5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylate Intermediate20 (100 mg, 0.42 mmol) and 5-oxa-8-azaspiro[3.5]nonane (160 mg, 1.26mmol) in DMF (5 ml) was stirred at 80° C. for 4 h. The crude product waspurified by preparative HPLC, PrepMethod E, (gradient: 38-50%) to givethe title compound (42 mg, 30%) as a white solid; HRMS (ESI) m/z [M+H]⁺calcd for C₁₆H₁₇FN₃O₄: 334.1198, found: 334.1176; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.54-1.85 (2H, m) 1.87-2.12 (4H, m) 3.58-3.67 (3H, m)3.71 (1H, s) 3.91-4.02 (2H, m) 7.35-7.47 (1H, m) 7.47-7.56 (1H, m)7.61-7.70 (1H, m) 10.49-10.75 (1H, m).

Example 91:5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-H-tetrazol-5-yl)-1,3,4-oxadiazole-2-carboxamide

Me₃Al (1 M in heptane, 2.52 mL, 2.52 mmol) was added dropwise to amixture of methyl5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylate Intermediate20 (200 mg, 0.84 mmol) and N-methyl-1-phenyl-1H-tetrazol-5-amineIntermediate 45 (441 mg, 2.52 mmol) in DCM (2 ml) and THF (10 ml) at 25°C. under an atmosphere of N₂(g). The resulting mixture was stirred at25° C. for 3 days. The reaction mixture was poured into 0.1 M HCl (100ml) and extracted with EtOAc (3×50 mL). The organic layer was dried overNa₂SO₄, filtered and evaporated. The solid was purified by preparativeHPLC, PrepMethod V, (gradient: 50-65%) to give the title compound (112mg, 35%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₁₇H₁₃FN₇O₃:382.1058, found: 382.1036; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.35 (3H, s)7.32-7.45 (2H, m) 7.47-7.64 (6H, m) 10.65 (1H, s).

Example 92:5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-H-tetrazol-5-yl)-1,2,4-oxadiazole-3-carboxamide

Me₃Al (2 M in hexane, 3425 μl, 6.85 mmol) was added to a mixture ofethyl 5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 39 (288 mg, 1.14 mmol) andN-methyl-1-phenyl-1H-tetrazol-5-amine Intermediate 45 (200 mg, 1.14mmol) in THF (20 mL). The resulting mixture was stirred at 60° C. for 16h. The reaction mixture was poured into 2 M HCl (10 mL) and extractedwith EtOAc (3×25 mL). The organic layer was dried over Na₂SO₄, filteredand evaporated. The crude orange oil was purified by flashchromatography on silica (gradient: 40-50% EtOAc in PE) to give thetitle compound (0.225 g, 51%) as a white solid; HRMS (ESI) m/z [M+H]⁺calcd for C₁₇H₁₃FN₇O₃: 382.1058, found: 382.1058; ¹H NMR (400 MHz,CD₃OD) δ 3.45 (3H, s), 7.22-7.30 (1H, m), 7.44-7.57 (2H, m), 7.62 (5H,s).

Example 93:(S)-(3-Phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(S)-3-Phenoxypyrrolidine (250 mg, 1.53 mmol) was added to a mixture ofDIPEA (990 mg, 7.66 mmol), HATU (1165 mg, 3.06 mmol) and5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (598 mg, 2.30 mmol) in DMF (5 mL). The reaction mixturewas stirred vigorously at 25° C. for 3 h. The reaction mixture wasquenched with water (50 mL) and extracted with EtOAc (3×50 mL). Theorganic layer was dried over MgSO₄, filtered and evaporated. The solidwas purified by preparative HPLC, PrepMethod Z (gradient: 50-65%) togive the title compound (0.040 g, 6%) as an off-white solid; HRMS (ESI)m/z [M+H]⁺ calcd for C₁₉H₁₅F₃N₃O₄: 406.1008, found: 406.1008; ¹H NMR(300 MHz, DMSO-d₆) δ ppm 2.09-2.37 (2H, m) 3.52-4.17 (4H, m) 5.05-5.22(1H, m) 6.88-7.04 (3H, m) 7.23-7.37 (2H, m) 7.52-7.72 (1H, m).

Example 94:(3-(Benzyloxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

3-(Benzyloxy)piperidine (1 g, 5.23 mmol) was added to a mixture of DIPEA(3.38 g, 26.14 mmol), HATU (3.98 g, 10.46 mmol) and5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (2.040 g, 7.84 mmol) in DMF (20 mL). The reaction mixturewas stirred vigorously at 25° C. for 3 h. The reaction mixture wasquenched with water (50 ml) and extracted with EtOAc (3×50 mL). Theorganic layer was dried over MgSO₄, filtered and evaporated. The solidwas purified by preparative HPLC, PrepMethod X (gradient: 28-38%) togive the title compound (33.5 mg, 1%) as an off-white solid; HRMS (ESI)m/z [M+H]⁺ calcd for C₂₁H₁₉F₃N₃O₄: 434.1322, found: 434.1314; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.37-1.56 (1H, m) 1.66-1.98 (2H, m) 3.37-3.65(4H, m) 3.73-3.84 (2H, m) 4.41 (1H, s) 4.49-4.67 (1H, m) 6.76-7.92 (5H,m).

Example 95:(R)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

COMU (884 mg, 2.06 mmol) was added to a mixture of(R)-3-(4-chlorophenyl)pyrrolidine (250 mg, 1.38 mmol),5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (358 mg, 1.38 mmol) and DIPEA (2.40 mL, 13.76 mmol) inDMF (2.5 ml) under an atmosphere of N₂(g). The resulting mixture wasstirred at 25° C. for 2 h. The reaction mixture was quenched with satbrine (50 mL) and extracted with EtOAc (3×50 mL). The organic layer wasdried over Na₂SO₄, filtered and evaporated. The yellow oil was purifiedby flash chromatography on a C18 column (gradient: 40-60% MeCN in water)to give the title compound (0.076 g, 13%) as a yellow solid; HRMS (ESI)m/z [M+H]⁺ calcd for C₁₉H₁₄ClF₃NO₃: 424.0670, found: 424.0668; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.96-2.15 (1H, m) 2.25-2.39 (1H, m) 3.40-3.99(4H, m) 4.02-4.22 (1H, m) 7.30-7.46 (4H, m) 7.59-7.78 (1H, m) 11.68 (1H,s).

Example 96:(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Me₃Al (2 M in toluene, 3460 μL, 6.92 mmol) was added to a mixture of5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (300 mg, 1.15 mmol) and 3-phenylpyrrolidine (340 mg, 2.31mmol) in THF (3 mL) at 25° C. under an atmosphere of N₂(g). Theresulting solution was stirred at 60° C. for 3 h. The reaction mixturewas acidified with 2 M HCl and then concentrated. The residue wasdiluted with EtOAc and washed sequentially with water and sat NaHCO₃.The organic layer was dried over Na₂SO₄, filtered and evaporated. Thecrude product was purified by preparative HPLC, PrepMethod E (gradient:55-70%) to give the title compound (0.030 g, 6%) as a white solid; HRMS(ESI) m/z [M+H]⁺ calcd for C₁₉H₁₅F₃N₃O₃: 390.1060, found: 390.1070; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.04-2.13 (1H, m) 2.29-2.36 (1H, m)3.46-3.51 (1H, m) 3.55-3.65 (1H, m) 3.73-3.86 (1H, m) 3.90-3.99 (1H, m)4.06-4.20 (1H, m) 7.21-7.29 (1H, m) 7.30-7.41 (4H, m) 7.58-7.71 (1H, m)11.61-11.77 (1H, m).

Example 97:(3-(Benzyloxy)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Me₃Al (2 M in toluene, 4613 μL, 9.23 mmol) was added to5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (400 mg, 1.54 mmol) and 3-(benzyloxy)pyrrolidine (273 mg,1.54 mmol) in DMF (5 ml) at 25° C. under an atmosphere of N₂(g). Theresulting solution was stirred at 25° C. for 2 h. The reaction mixturewas acidified with 2 M HCl and then concentrated. The residue wasdiluted with EtOAc, and washed sequentially with water. The organiclayer was dried over Na₂SO₄, filtered and evaporated to give a crudeproduct that was purified by preparative HPLC, PrepMethod V (gradient:50-62%) to give the title compound (0.048 g, 7%) as a white solid; HRMS(ESI) m/z [M+H]⁺ calcd for C₂₀H₁₇F₃N₃O₄: 420.1166, found: 420.1168; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.99-2.22 (2H, m) 3.53-3.88 (4H, m)4.23-4.36 (1H, m) 4.45-4.65 (2H, m) 7.26-7.45 (5H, m) 7.49-7.73 (1H, m)11.43 (1H, s).

Example 98:(R)-(3-Phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(R)-3-Phenoxypyrrolidine (300 mg, 1.84 mmol) was added to a mixture of5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (1.195 g, 4.60 mmol), HATU (1.398 g, 3.68 mmol) and DIPEA(963 μl, 5.51 mmol) in DMF (10 ml) at 0° C. under an atmosphere ofN₂(g). The resulting mixture was stirred at 25° C. for 3 h. The reactionmixture was concentrated, diluted with DCM (50 ml) and washedsequentially with water (3×50 ml) and sat brine (3×50 mL). The organiclayer was dried over Na₂SO₄, filtered and evaporated. The residue waspurified by preparative TLC (DCM:MeOH, 20:1) and then by preparativeHPLC, PrepMethod N (gradient: 50-65%) to give the crude compound. Thecrude was diluted with DCM (100 mL) and washed sequentially with satNaHCO₃ (3×100 mL) and water (3×100 mL). The organic layer was dried overNa₂SO₄, filtered and evaporated. As the residue still containedimpurities it was again diluted with DCM and washed as above with satNaHCO₃ and water, dried over Na₂SO₄, filtered and evaporated to give thetitle compound (0.031 g, 34%) as a white solid; HRMS (ESI) m/z [M+H]⁺calcd for C₁₉H₁₅F₃N₃O₄: 406.1008, found: 406.1040; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.12-2.32 (2H, m) 3.59-3.71 (1H, m) 3.72-4.10 (3H, m)5.15 (1H, br s) 6.90-7.06 (3H, m) 7.24-7.39 (2H, m) 7.57-7.77 (1H, m)11.52 (1H, br s).

Example 99:N-(1-Cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxamide

1-Cyclohexyl-1H-pyrazol-5-amine (120 mg, 0.73 mmol) was added to amixture of HATU (387 mg, 1.02 mmol), DIPEA (634 μL, 3.63 mmol) and5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid Intermediate 34(211 mg, 0.94 mmol) in DMF (5 mL). The resulting mixture was stirred at25° C. for 3 h. Water was added and the aqueous layer was extracted withEtOAc (×3). The combined organic layer was washed with sat NaHCO₃ (aq,×2), dried over anhydrous Na₂SO₄ and evaporated to dryness. The residuewas purified by preparative TLC (PE:EtOAc, 1:1) followed by flashchromatography on a C18 column (gradient: 0-100% MeCN in water) to givethe title compound (0.072 g, 26%) as a white solid; HRMS (ESI) m/z[M+H]⁺ calcd for C₁₉H₂₀FN₄O₃: 371.1514, found: 371.1514; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.09-1.42 (3H, m) 1.64 (1H, br d) 1.69-1.93 (6H, m)4.01-4.18 (1H, m) 6.21 (1H, d) 7.32-7.40 (1H, m) 7.41-7.48 (3H, m) 7.51(1H, dd) 10.43 (1H, br s) 10.74 (1H, br s).

Example 100:N-((1-Cyclohexy-1H-pyrazol-5-y)methyl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide

2,6-Dimethylpyridine (130 μL, 1.12 mmol) was added to a mixture of2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxylic acid Intermediate 41(50 mg, 0.22 mmol), (1-cyclohexyl-1H-pyrazol-5-yl)methanamine (40.2 mg,0.22 mmol) and HATU (94 mg, 0.25 mmol) in DMF (2.11 mL). The reactionwas left at rt overnight. The reaction was diluted with EtOAc (20 mL),washed with sat NaHCO₃ (10 mL) and brine (3×10 mL). The organic layerwas dried over MgSO₄, filtered and concentrated under reduced pressure.The crude product was purified by preparative HPLC, PrepMethod SFC-A(gradient: 5-90%) to give the title compound (10.90 mg, 12%); HRMS (ESI)m/z [M+H]⁺ calcd for C₂₀H₂₂FN₄O₃: 385.1670, found: 385.1660; ¹H NMR (600MHz, DMSO-d₆) δ 9.18 (t, 1H), 7.89 (s, 1H), 7.69 (dd, 1H), 7.56 (ddd,1H), 7.32-7.37 (m, 2H), 6.17 (d, 1H), 4.56 (d, 2H), 4.2-4.26 (m, 1H),4.09 (s, 1H), 1.74-1.83 (m, 6H), 1.64 (d, 1H), 1.35 (qt, 2H), 1.17 (qt,1H).

Example 101:(R)-(5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone

(R)-3-Phenylpyrrolidine (100 mg, 0.68 mmol) was added to a mixture ofCOMU (291 mg, 0.68 mmol), DIPEA (263 mg, 2.04 mmol) and5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid Intermediate 34(182 mg, 0.82 mmol) in DMF (5 mL). The reaction mixture was stirredvigorously at 25° C. for 3 h. The solvent was removed under reducedpressure and the crude product was purified by flash chromatography on aC18 column (gradient: 0-60% MeCN in water) followed by preparative HPLC,PrepMethod Y (gradient: 32-62%) to give the title compound (0.037 g,15%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₁₈FN₂O₃:353.1296, found: 353.1304; ¹H NMR (300 MHz, DMSO-d) δ ppm 1.96-2.18 (1H,m) 2.22-2.43 (1H, m) 3.42-3.68 (2H, m) 3.71-3.88 (1H, m) 3.93-4.10 (1H,m) 4.23 (1H, dd) 6.90-7.82 (9H, m).

Example 102:(3H-Spiro[isobenzofuran-1,3′-pyrrolidin]-1′-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

DIC (89 μL, 0.57 mmol) was added to a mixture of3H-spiro[isobenzofuran-1,3′-pyrrolidine] (50 mg, 0.29 mmol),5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (74.2 mg, 0.29 mmol) in DMF (1 mL) at 0° C. under anatmosphere of N₂(g). The resulting mixture was stirred at 25° C. for 16h. The reaction mixture was quenched with sat NaHCO₃ (25 mL) andextracted with EtOAc (3×25 mL). The combined organic layer was driedover Na₂SO₄, filtered and evaporated. The crude product was purified byflash chromatography on a C18 column (gradient: 60-70% MeCN in water) togive the title compound (9 mg, 7%) as a white solid; HRMS (ESI) m/z[M+H]⁺ calcd for C₂₀H₁₅F₃N₃O₄: 418.1008, found: 418.1014; ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.13-2.26 (1H, m) 2.37-2.48 (1H, m) 3.66-4.01 (3H,m) 4.06 (1H, t) 4.97-5.18 (2H, m) 7.27-7.42 (3H, m) 7.44-7.62 (2H, m).

Example 103:(S)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(S)-3-(4-Chlorophenyl)pyrrolidine (200 mg, 1.10 mmol) was added to amixture of DIPEA (427 mg, 3.30 mmol), HATU (837 mg, 2.20 mmol) and5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (430 mg, 1.65 mmol) in DMF (10 mL). The reaction mixturewas stirred vigorously at rt for 3 h, then quenched with sat brine (50mL) and extracted with EtOAc (3×50 mL). The combined organic layer wasdried over Na₂SO₄, filtered and evaporated. The yellow oil was purifiedby preparative HPLC, PrepMethod Y (gradient: 28-38%) to give the titlecompound (0.039 g, 8%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd forC₁₉H₁₄ClF₃NO₃: 424.0670, found: 424.0676; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.96-2.17 (1H, m) 2.25-2.42 (1H, m) 3.41-3.99 (4H, m) 4.12 (1H, ddd)7.29-7.51 (4H, m) 7.53-7.82 (1H, m) 11.73 (1H, br s).

Example 104:(R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone

EDC (118 mg, 0.62 mmol) and HOBt (83 mg, 0.62 mmol) were added to amixture of 5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylicacid Intermediate 37 (80 mg, 0.31 mmol), (R)-3-phenylpyrrolidine (45.4mg, 0.31 mmol), DIPEA (162 μL, 0.93 mmol) and DMAP (7.54 mg, 0.06 mmol)in DMF (2 ml) at 20° C. The resulting solution was stirred at 60° C. for3 h under an atmosphere of N₂(g). The reaction mixture was concentrated,diluted with EtOAc (25 ml) and washed with water (25 mL). The organiclayer was dried over Na₂SO₄, filtered and evaporated. The residue waspurified by preparative TLC (MeOH:DCM, 1:10) followed by preparativeHPLC, PrepMethod N (gradient: 45-55%) to give the title compound (0.018g, 15%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₁₆F₃N₂O₃:389.1108, found: 389.1094; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.96-2.19(1H, m) 2.30-2.43 (1H, m) 3.40-4.29 (5H, m) 7.16 (1H, d) 7.22-7.31 (1H,m) 7.31-7.39 (4H, m) 7.40-7.64 (1H, m) 11.56 (1H, br s).

Example 105:N,N-Dimethyl-1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide

BBr₃ (1 M in DCM, 0.2 mL, 0.20 mmol) was added dropwise toN,N-dimethyl-1-(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamideIntermediate 48 (50 mg, 0.12 mmol) in DCM (1 ml) at 0° C. under anatmosphere of N₂(g). The resulting solution was stirred at 20° C. for 8h. The reaction was quenched with MeOH (2 mL). The residue was purifiedby preparative TLC (MeOH:DCM, 1:10) followed by preparative HPLC,PrepMethod N, (gradient: 31-44%) to give the title compound (0.014 g,29%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₁₈H₁₈F₃N₂O₃S:399.0984, found: 399.0976; Mixture of rotamers: ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.69-1.84 (1H, m) 1.89-2.11 (2H, m) 2.14-2.31 (1H, m)2.76-2.88 (3H, m) 2.96-3.17 (3H, m) 3.53-3.72 (0.4H, m) 3.78-4.02 (1.6H,m) 4.96 (0.8H, dd) 5.27 (0.2H, dd) 7.18-7.79 (3H, m) 11.27 (1H, s).Total no of protons in spectrum: 17.

Example 106:2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)isoindoline-5-carbonitrile

5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (34 mg, 0.13 mmol), HATU (99 mg, 0.26 mmol) and DMF (0.5ml) were mixed in a vial. Isoindoline-5-carbonitrile HCl (23.61 mg, 0.13mmol) dissolved in DMF (0.500 ml) was added followed by DIPEA (137 μL,0.78 mmol). The resulting yellow solution was stirred at rt overnight.The reaction mixture was diluted with DMSO and purified by preparativeHPLC, PrepMethod C (gradient: 15-60%) to give the title compound (0.012g, 24%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₁₈H₁₀F₃N₄O₃:387.0700, found: 387.0686; ¹H NMR (500 MHz, DMSO-d₆) δ 4.99 (2H, d),5.22 (2H, d), 7.56-7.7 (2H, m), 7.77-7.84 (1H, m), 7.91 (1H, d).

Example 107:(4-(3-Isopropyl-1,2,4-oxadiazol-5-yl)-3,6-dihydropyridin-1(2H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Me₃Al (2 M in toluene, 0.985 mL, 1.97 mmol) was added to3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,4-oxadiazoleIntermediate 51 (198 mg, 1.02 mmol) in toluene (2 mL) under anatmosphere of N₂(g). The resulting mixture was stirred at rt for 45 min.The mixture was added to a stirred slurry of ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (227 mg, 0.79 mmol) in toluene (2 mL). The resultingmixture was heated to 60° C. for 5 h, then cooled to rt. Tartaric acid(30%, aq, 12 mL) was added and the mixture was extracted with EtOAc(×2). The combined organic layer was concentrated under reduced pressureand the residue was purified by preparative HPLC, PrepMethod C(gradient: 35-75%) to give the title compound (209 mg, 61%) as anoff-white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₁₇F₃N₅O₄: 436.1228,found: 436.1210; Mixture of rotamers: ¹H NMR (500 MHz, MeOD) 1.33 (6H,dd), 2.74-2.82 (2H, m), 3.03-3.12 (1H, m), 3.92 (1.3H, t), 4.05 (0.7H,t), 4.51-4.57 (2H, m), 6.95-7 (0.4H, m), 7.07-7.11 (0.6H, m), 7.51-7.6(1H, m). Total no of protons in spectrum: 15.

Example 108:((2S,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazol-3-yl)methanone

A mixture of((2S,6R)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanoneExample 87 (29 mg, 0.08 mmol) and NIS (73.0 mg, 0.32 mmol) in AcOH (2mL) was stirred at rt for 20 h. The mixture was concentrated and theresidue was diluted with MeCN and DMSO and purified by preparative HPLC,PrepMethod C (gradient: 20-80%) to give the title compound (27 mg, 68%)as a brown-yellow solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₁₅H₁₄F₃IN₃O₄:483.9976, found: 483.9962; ¹H NMR (500 MHz, CDCl₃) δ 1.22 (3H, d), 1.29(3H, d), 2.6-2.72 (2H, m), 3.00 (1H, dd), 3.6-3.81 (2H, m), 4.20 (1H,dt), 4.63 (1H, dt).

Example 109:2-(5-(2,4,5-Trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile

A mixture of2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrileExample 66 (0.149 g, 0.24 mmol) and NIS (0.218 g, 0.97 mmol) in AcOH (10ml) was stirred at rt for 20 h. The mixture was concentrated and theresidue purified by preparative HPLC, PrepMethod D (gradient: 20-80%) togive the title compound (0.063 mg, 50%) as a white solid; HRMS (ESI) m/z[M+H]⁺ calcd for C₁₉H₁₁F₃IN₄O₃: 526.9822, found: 526.9808; ¹H NMR (500MHz, CDCl₃) 3.26 (2H, t), 4.14 (2H, t), 5.01 (2H, s), 7.38 (1H, t), 7.46(1H, d), 7.59 (1H, d), 9.23 (1H, s).

Example 110:((2R,6S)-2,6-Dimethylmorpholino)₃-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone

Me₃Al (2 M in toluene, 0.347 mL, 0.69 mmol) was added dropwise under anatmosphere of N₂(g) and at rt to a solution of(2R,6S)-2,6-dimethylmorpholine (0.048 mL, 0.38 mmol) in anhydroustoluene (0.5 mL). The reaction mixture was stirred at rt for 1 h. andwas then added dropwise at rt to a stirred mixture of methyl3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylateIntermediate 52 (80 mg, 0.29 mmol) in toluene (0.75 ml) under anatmosphere of N₂(g). The resulting solution was heated at 60° C. for 6 hand was then cooled to 0° C. Tartaric acid (30%, aq, 4 ml) was addeddropwise and the resulting mixture was extracted with EtOAc (×2). Thecombined organic layer was washed with H₂O (×2), passed through a phaseseparator, and concentrated under reduced pressure. The residue waspurified by preparative HPLC, PrepMethod D, (gradient: 25-65%) to givethe title compound (52 mg, 49%) as a white solid; HRMS (ESI) m/z [M+H]⁺calcd for C₁₅H₁₅F₃N₃O₄: 358.1008, found: 358.1022; ¹H NMR (500 MHz,DMSO-d₆) δ 1.08 (3H, d), 1.17 (3H, d), 2.64 (1H, dd), 2.95 (1H, dd),3.56-3.66 (2H, m), 4.1-4.17 (1H, m), 4.32-4.38 (1H, m), 7.48 (1H, ddd),11.50 (1H, s).

Example 111:((3R,5S)-3,5-Dimethylpiperidin-1-yl)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone

The title compound was prepared from methyl3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylateIntermediate 52 (80 mg, 0.29 mmol) and (3S,5R)-3,5-dimethylpiperidine(44 mg, 0.39 mmol) in analogy to the preparation of Example 110. Thecrude product was purified by preparative HPLC, PrepMethod D, (gradient:35-75%) to give the title compound (67 mg, 65%) as a white solid; HRMS(ESI) m/z [M+H]⁺ calcd for C₁₆H₁₇FN₃O₃: 356.1216, found: 356.1224; ¹HNMR (500 MHz, DMSO-d₆) δ 0.83 (3H, d), 0.84-0.91 (1H, m), 0.93 (3H, d),1.57-1.72 (2H, m), 1.77-1.84 (1H, m), 2.42 (1H, t), 2.74 (1H, dd),3.89-3.96 (1H, m), 4.37-4.45 (1H, m), 7.45 (1H, ddd), 11.47 (1H, s).

Example 112:((4aR,7aS)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(4aR,7aS)-Octahydrocyclopenta[b][1,4]oxazine HCl (0.052 g, 0.32 mmol)was dissolved in MeOH and passed through an Isolute NH₂ column (1 g).The compound was eluted with MeOH. The MeOH was evaporated and theresidue was dissolved in dry toluene (0.5 mL). Me₃Al (2 M in toluene,0.304 mL, 0.61 mmol) was added dropwise at rt under a N₂(g) atmosphere.The solution was stirred at rt for 45 min, then added dropwise at rt toa stirred solution of ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (0.07 g, 0.24 mmol) in toluene (0.6 ml) under nitrogen.The solution was heated to 60° C. for 20 h. Tartaric acid (30%, aq, 5ml) was added dropwise. The mixture was extracted with EtOAc. The phaseswere separated and the water phase was extracted again with EtOAc. Theorganic phases were combined and concentrated under reduced pressure.The residue was dissolved in DMSO and purified by preparative HPLC,PrepMethod D (gradient: 30-100%) to give the title compound (0.032 g,36%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₁₆H₁₅F₃N₃O₄:370.1014, found: 370.0996; Mixture of rotamers: ¹H NMR (500 MHz,DMSO-d₆) δ 1.42-2.13 (6H, m), 3.1-3.19 (0.6H, m), 3.37-3.51 (1.4H, m),3.58 (0.4H, d), 3.71-3.79 (1H, m), 3.83-3.97 (1.6H, m), 4.16 (0.6H, dd),4.48-4.57 (0.4H, m), 7.51-7.8 (1H, m), 11.71 (1H, s). Total number ofprotons in spectrum: 14.

Example 113:((4aS,7aR)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(4aS,7aR)-Octahydrocyclopenta[b][1,4]oxazine HCl (0.052 g, 0.32 mmol)was dissolved in MeOH and passed through an Isolute NH₂ ion exchangecolumn (1 g). The compound was eluted with MeOH. The MeOH was evaporatedand the residue was dissolved in dry toluene (0.5 mL). Me₃Al (2 M intoluene, 0.304 mL, 0.61 mmol) was added dropwise under a N₂ (g)atmosphere at rt. The solution was stirred at rt for 45 min, then addeddropwise at rt to a stirred solution of ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (0.07 g, 0.24 mmol) in toluene (0.6 ml) under anatmosphere of N₂(g). The solution was heated to 60° C. for 20 h.Tartaric acid (30%, aq, 5 ml) was added dropwise. The mixture wasextracted with EtOAc. The phases were separated and the water phase wasextracted again with EtOAc. The organic phases were combined andconcentrated under reduced pressure. The residue was dissolved in DMSOand purified by preparative HPLC, PrepMethod D (gradient: 30-100%), togive the title compound (0.032 g, 36%) as a white solid; HRMS (ESI) m/z[M+H]⁺ calcd for C₁₆H₁₅F₃N₃O₄: 370.1014, found: 370.1002; Mixture ofrotamers: ¹H NMR (500 MHz, DMSO-d₆) δ 1.44-2.04 (6H, m), 3.08-3.21(0.6H, m), 3.36-3.51 (1.4H, m), 3.55-3.61 (0.4H, m), 3.71-3.8 (1H, m),3.83-3.99 (1.6H, m), 4.16 (0.6H, dd), 4.43-4.65 (0.4H, m), 7.52-7.82(1H, m), 11.68 (1H, s). Total number of protons in spectrum: 14.

Example 114:((4aR,7aR)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(4aR,7aR)-Octahydrocyclopenta[b][1,4]oxazine (0.040 g, 0.32 mmol) wasdissolved in dry toluene (0.5 ml). Me₃Al (2 M in toluene, 0.304 ml, 0.61mmol) was added dropwise at rt under an atmosphere of N₂(g). Theresulting solution was stirred at rt for 45 min, then added dropwise toa stirred solution of ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (0.07 g, 0.24 mmol) in toluene (0.6 ml) under anatmosphere of N₂(g). The solution was heated to 60° C. for 20 h.Tartaric acid (30%, aq, 5 ml) was added dropwise and the mixture wasextracted with EtOAc. The aqueous layer was extracted with EtOAc. Thecombined organic layer was concentrated under reduced pressure. Theresidue was dissolved in DMSO and purified by preparative HPLC,PrepMethod C (gradient: 30-100%), to give the title compound (0.023 g,26%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₁₆H₁₅F₃N₃O₄:370.1014, found: 370.1024; Mixture of rotamers, ¹H NMR (500 MHz,DMSO-d₆) δ 1.03-2.01 (6H, m), 3.03-3.28 (2H, m), 3.37-3.52 (1H, m),3.54-3.78 (1.7H, m), 3.8-4.11 (1H, m), 4.32-4.46 (0.3H, m), 7.57-7.8(1H, m), 11.70 (1H, s). Total number of protons in spectrum: 14.

Example 115:((4aS,7aS)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (0.08 g, 0.31 mmol), HATU (0.234 g, 0.62 mmol) and DMF(1.2 ml) were mixed in a vial.(4aS,7aS)-Octahydrocyclopenta[b][1,4]oxazine HCl Bioorganic & MedicinalChemistry Letters (2015), 25(5), 1086-1091 (0.050 g, 0.31 mmol) wasadded followed by DIPEA (0.322 ml, 1.85 mmol)). The resulting yellowsolution was stirred at rt for 4 h. The reaction mixture was dilutedwith DMSO and purified by preparative HPLC, PrepMethod D (gradient:30-100%), to give the title compound (0.039 g, 34%) as a light yellowsolid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₆H₁₅F₃N₃O₄: 370.1014, found:370.0981; Mixture of rotamers, ¹H NMR (500 MHz, DMSO-d₆) δ 0.98-2.01(6H, m), 2.98-3.27 (2H, m), 3.36-3.53 (1H, m), 3.51-3.79 (1.7H, m),3.79-4.19 (1H, m), 4.40 (0.3H, s), 7.51-7.84 (1H, m), 11.70 (1H, s).Total number of protons in spectrum: 14.

Example 116:(5-(3,4-Difluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2R,6S)-2,6-dimethylmorpholino)methanone

Me₃Al (2 M in toluene, 0.407 ml, 0.81 mmol) was added to a stirredsolution of (2S,6R)-2,6-dimethylmorpholine (0.076 ml, 0.63 mmol) intoluene (1 ml) under an atmosphere of N₂(g) and the resulting mixturewas stirred at rt for 1 h. The mixture was added to a stirred slurry ofethyl 5-(3,4-difluoro-5-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 53 (0.100 g, 0.37 mmol) in toluene (1 ml), and theresulting mixture was heated to 60° C. for 22 h, and then cooled to rt.Tartaric acid (30%, aq, 5 ml) was added, and the mixture was extractedwith EtOAc (5 ml). The organic layer was concentrated, and the residuewas purified by preparative HPLC, PrepMethod C, (gradient: 50-80%) toyield the product (65 mg, 52%) as an off-white solid; HRMS (ESI) m/z[M+H]⁺; calcd for C₁₅H₁₆F₂N₃O₄: 340.1104, found: 340.1124; ¹H NMR (500MHz, DMSO-d₆) δ 1.04 (3H, d), 1.16 (3H, d), 2.59 (1H, dd), 2.86 (1H,dd), 3.55 (2H, dddt), 3.77 (1H, d), 4.36 (1H, d), 7.55 (1H, d), 7.62(1H, ddd), 11.29 (1H, s).

Example 117:(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2,2,6-trimethylmorpholino)methanone

2,2,6-Trimethylmorpholine (0.041 g, 0.32 mmol) was dissolved in drytoluene (0.5 ml). Me₃Al (2 M in toluene, 0.304 ml, 0.61 mmol) was addeddropwise at rt under an atmosphere of N₂(g). The resulting solution wasstirred at rt for 45 min, then added dropwise at rt to a stirredsolution of ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (0.07 g, 0.24 mmol) in toluene (0.6 ml) under anatmosphere of N₂(g). The solution was heated to 60° C. for 20 h.Tartaric acid (30%, aq, 5 ml) was added dropwise. The mixture wasextracted with EtOAc. The aqueous layer was extracted with EtOAc. Thecombined organic layer was concentrated under reduced pressure. Theresidue was dissolved in DMSO and purified by preparative HPLC,PrepMethod D (gradient: 35-85%), to give the title compound (0.034 g,38%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₁₆H₁₇F₃N₃O₄:372.1166, found: 372.1158; Mixture of rotamers: ¹H NMR (500 MHz,DMSO-d₆) δ 0.99 (1H, d), 1.05-1.13 (3H, m), 1.13-1.24 (5H, m), 2.56(0.7H, dd), 2.76 (0.4H, d), 2.83 (0.4H, dd), 3.02 (0.5H, d), 3.56 (0.5H,dd), 3.73-3.9 (1.5H, m), 4.23 (0.4H, dd), 4.36 (0.5H, dt), 7.51-7.84(1H, m). Total number of protons in spectrum: 15.

Example 118:(4-Oxa-7-azaspiro[2.5]octan-7-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acidIntermediate 2 (64 mg, 0.25 mmol), HATU (122 mg, 0.32 mmol) and DMF (1ml) were mixed in a vial. DIPEA (0.129 mL, 0.74 mmol)) was addedfollowed by 4-oxa-7-azaspiro[2.5]octane HCl (55.2 mg, 0.37 mmol). Theresulting solution was stirred at rt overnight. The reaction was dilutedwith DMSO and purified by preparative HPLC, PrepMethod C (gradient:20-80%), to give the title compound (20 mg, 23%) as a white solid; HRMS(ESI) m/z [M+H]⁺ calcd for C₁₅H₁₃F₃N₃O₄: 356.0852, found: 356.0854; ¹HNMR (500 MHz, DMSO-d₆) δ 0.56-0.61 (1H, m), 0.64-0.68 (1H, m), 0.68-0.74(1H, m), 0.74-0.79 (1H, m), 3.50 (1H, s), 3.65 (2H, s), 3.70 (1H, s),3.71-3.76 (1H, m), 3.76-3.8 (1H, m), 7.5-7.82 (1H, m), 11.67 (1H, s).

Example 119:((3R,5S)-3,5-Dimethylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

tert-Butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (0.145 g, 0.68mmol) was dissolved in dry toluene (1 mL). Me₃Al (2 M in toluene, 0.651mL, 1.30 mmol) was added dropwise at rt under an atmosphere of N₂(g).The resulting solution was stirred at rt for 45 min, then added dropwiseto a stirred solution of ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (0.15 g, 0.52 mmol) in toluene (1.3 mL) under nitrogen.The solution was heated to 60° C. for 20 h. Tartaric acid (30%, aq, 5mL) was added dropwise. The aqueous phase was washed with EtOAc. Theaqueous phase was purified by preparative HPLC, PrepMethod D (gradient:5-45%), to give the title compound (0.126 g, 68%) as a white solid; HRMS(ESI) m/z [M+H]⁺ calcd for C₁₅H₁₆F₃N₄O₃: 357.1168, found: 357.1158; ¹HNMR (500 MHz, DMSO-d₆) δ 1.03 (3H, d), 1.15 (3H, d), 2.56-2.69 (1H, m),2.84-3.09 (3H, m), 3.86 (1H, d), 4.47 (1H, d), 7.16-7.46 (1H, m).

Example 120:((2R,6S)-2,6-Dimethylmorpholino)₂-(2,4,5-trifluoro-3-hydroxyphenyl)thiazol-5-yl)methanone

BBr₃ (1 M in DCM, 1.025 mL, 1.02 mmol) was added dropwise to a solutionof((2S,6R)-2,6-dimethylmorpholino)(2-(2,4,5-trifluoro-3-methoxyphenyl)thiazol-5-yl)methanoneIntermediate 56 (132 mg, 0.34 mmol) in DCM (5 mL) at 0° C. The reactionmixture was stirred for 2 h at rt. Additional BBr₃ (1 M in DCM, 1.025mL, 1.02 mmol) was added dropwise and stirring was continued for 1.5 h.The reaction mixture was diluted with DCM, cooled by an ice-bath andwater was carefully added. The organic layer was separated and theaqueous layer was extracted with EtOAc (×2). The combined organic layerwas passed through a phase separator and concentrated. The residue waspurified by preparative HPLC, PrepMethod J, (gradient: 30-70%) to givethe title compound (86 mg, 68%) as a white solid; HRMS (ESI) m/z [M+H]⁺calcd for C₁₆H₁₆F₃N₂O₃S: 373.0834, found: 373.0821; ¹H NMR (500 MHz,DMSO, 25° C.) δ 0.72-1.35 (6H, m), 2.46-3.14 (overlapping with solvent,m), 3.54-3.64 (2H, m), 3.8-4.51 (2H, m), 7.62 (1H, ddd), 8.30 (1H, d),11.45 (1H, s).

Example 121:rac-((2R,6S)-2-Ethyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(Racemic)

2 M AlMe₃ in toluene (2.17 mL, 4.34 mmol) was added dropwise under N₂ atrt to a solution of rac-(2R,6S)-2-ethyl-6-methylmorpholine (314 mg, 2.43mmol) in anhydrous toluene (2.5 mL). The resulting solution was stirredfor 1 h and was then added dropwise at rt to a stirred mixture of ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (500 mg, 1.74 mmol) in anhydrous toluene (3.5 mL) underN₂. The resulting solution was stirred at 60° C. for 7.5 h. The reactionwas allowed to cool to rt overnight and was then further cooled to 0° C.30% tartaric acid (aq, 25 mL) was added dropwise and the resultingmixture was extracted with EtOAc (×2). The organic layers were combined,washed with H₂O, passed through a phase separator and concentrated underreduced pressure. The residue was purified by preparative HPLC,PrepMethod D, (gradient 0-75%, then 100%) to give the title compound (62mg, 10%) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd for C₁₆H₁₇ F₃N₃O₄: 372.1171, found: 372.1156; ¹H NMR (500 MHz, DMSO, 25° C., mixtureof rotamers) δ 0.85 (1.4H, t), 0.93 (1.6H, t), 1.05 (1.6H, d), 1.17(1.4H, d), 1.34-1.43 (1H, m), 1.46-1.56 (1H, m), 2.07 (OH, s), 2.62 (1H,ddd), 2.89 (1H, ddd), 3.34-3.4 (1H, m), 3.46-3.61 (1H, m), 3.73-3.82(1H, m), 4.34-4.42 (1H, m), 7.61-7.69 (1H, m), 11.68 (1H, s).

Example 122rac-((2R,6S)-2-isopropyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(Racemic)

2 M AlMe₃ in toluene (2.17 mL, 4.34 mmol) was added dropwise under N₂ atrt to a solution of rac-(2R,6S)-2-isopropyl-6-methylmorpholine (348 mg,2.43 mmol) in anhydrous toluene (2.5 mL). The resulting solution wasstirred at rt for 1 h and was then added dropwise at rt to a stirredmixture of ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (500 mg, 1.74 mmol) in anhydrous toluene (3.5 ml) underN₂. The resulting solution was stirred at 60° C. for 7.5 h. The reactionwas allowed to cool to rt overnight and then further cooled to 0° C. 30%tartaric acid (aq, 25 ml) was added dropwise and the mixture wasextracted with EtOAc (×2). The organic layers were combined and washedwith H₂O, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC, PrepMethod D,(gradient 40-80%) to give the title compound (367 mg, 55%) as a whitesolid; HRMS (ESI) m/z [M+H]⁺ calcd for C17H19 F3 N3 O4: 386.1328, found:386.1328; ¹H NMR (500 MHz, DMSO, 25° C., mixture of rotamers) δ 0.83(1.3H, d), 0.88 (1.3H, d), 0.93 (1.7H, d), 0.96 (1.7H, d), 1.05 (1.7H,d), 1.18 (1.3H, d), 1.59-1.68 (0.4H, m), 1.69-1.77 (0.6H, m), 2.61(0.4H, dd), 2.69 (0.6H, dd), 2.87 (0.6H, dd), 2.96 (0.4H, dd), 3.14-3.23(1H, m), 3.45-3.62 (1H, m), 3.76 (0.6H, dt), 3.84 (0.4H, dt), 4.34-4.45(1H, m), 7.6-7.69 (1H, m), 11.5-11.88 (1H, m).

Example 123(6-Methyl-5-oxa-8-azaspiro[3.5]nonan-8-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

(Racemic)

2 M AlMe₃ (1.09 ml, 2.17 mmol) was added dropwise under N₂ at rt to asolution of rac-(R)-6-methyl-5-oxa-8-azaspiro[3.5]nonane (172 mg, 1.21mmol) in anhydrous toluene. The resulting solution was stirred at rt for1 h and was then added dropwise at rt to a stirred mixture of ethyl5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylateIntermediate 1 (0.25 g, 0.87 mmol) in anhydrous toluene (1.75 ml) underN₂. The resulting solution was heated at 60° C. for 4 h. The heat wasturned off and the reaction was allowed to cool to rt overnight and thenfurther cooled to 0° C. 30% tartaric acid (aq, 13 ml) was added dropwiseand the mixture was extracted with EtOAc (×2). The organic layers werecombined, washed with water, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC, PrepMethod J, (gradient: 35-75%). The fractionscontaining product were acidified to pH5 using HOAc and the MeCN wasremoved under reduced pressure. The resulting aqueous oil/water mixturewas extracted with DCM (×3). The combined organic layer was concentratedand the residue was purified by preparative HPLC, prepmethod D,(gradient: 35-75%) to give the title compound (208 mg, 63%) as a whitesolid; HRMS (ESI) m/z [M+H]⁺ calcd for C17H17 F3 N3 O4: 384.1171, found:384.1185; ¹H NMR (500 MHz, DMSO, 25° C., 3:2 mixture of rotamers) δ 1.02(1.3H, d), 1.13 (1.7H, d), 1.47-2.08 (5.4H, m), 2.13-2.22 (0.5H, m),2.62 (0.6H, dd), 2.82 (0.4H, dd), 2.89 (0.4H, dd), 3.05 (0.6H, dd),3.48-3.63 (1.1H, m), 3.74 (0.4H, dt), 3.84 (0.6H, dd), 4.31 (0.6H, dt),4.53 (0.4H, dd), 7.6-7.69 (1H, m), 11.72 (1H, s).

Example 124(5-(2-Bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-y)(2R,6S)-2,6-dimethylmorpholino)methanone

A mixture of((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanoneExample 87 (4.84 g, 13.6 mmol) and NBS (2.89 g, 16.26 mmol) in AcOH (50ml) was stirred at 80° C. for 20 min. The reaction mixture was allowedto cool to rt and was then concentrated under reduced pressure. Theresidue was dissolved in EtOAc (75 ml) and washed with water (5×50 ml).Small aliquots of 30% NaCl(aq), (typically 1-3 ml) was added to speed upphase separation. The organic layer was washed with 30% NaCl(aq), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe title compound (5.91 g, 100%) as a pale yellow solid foam.

A small part of the title compound (200 mg) was further purified bypreparative HPLC, PrepMethod D, gradient (30-70%) to give the titlecompound (133 mg) as a white solid; HRMS (ESI) m/z [M+H]⁺ calcd forC15H14 Br F3 N3 O4: 436.0120, found: 436.0116; ¹H NMR (500 MHz, DMSO,25° C.) δ 1.06 (3H, d), 1.17 (3H, d), 2.63 (1H, dd), 2.94 (1H, dd),3.54-3.65 (2H, m), 3.70 (1H, dt), 4.37 (1H, dt), 12.05 (1H, s).

In Vitro 17bHSD13 Enzyme Assay

10 concentration of compounds (0.2 μl) in DMSO was added to GREINER PP384 well plate (781280) using ECHO dispensing (BECKMAN COULTER) followedby 20 μl of recombinant 17bHSD13 (N2-K300). The enzyme reaction wasinitiated by addition, using CERTUS-FLEX dispenser (GYGER), of 20 μl ofsubstrate solution containing NAD (SIGMA, N1511) and Estradiol (SIGMA,E8875). After each addition plates were centrifuged for 1 min at 150×g(EPPENDORF, 5810R, A-4-81). Final assay conditions were 80 nM of17bHSD13, 0.5 mM of NAD, 20 μM Estradiol and various concentrations ofcompound in buffer (5 mM EDTA (TEKNOVA E0306), 0.01% DDM (AFFYMETRIXD310) in 50 mM Tris-Cl, pH 7.4). After 2.5 h the reaction were stoppedby addition of 20 μl of 0.6% Formic acid (MERCK 5.33002) and sampleswere analyzed using LC-MS/MS.

SCIEX LC-MS/MS system: Sample was injected with CTC analytical injector,SHIMATZU LC pumps LC20 and analyzed on the SCIEX API 5000 LCMSMS systemwith the following settings. Samples were chromatographed on a WATERS,SYMMETRY, C8, 3.5 μm, 2.1×50 mm) column at constant flow rate of 0.5mL/min. The mobile phases consist of A (water with 0.2% formic acid) andB (acetonitrile with 0.2% formic acid). The LC gradient profile is asfollows: 50% B during 0 to 0.5 min, a linear increase to 100% B during0.5 to 1 min, hold at 100% B during 1 to 1.6 min then back to 50% B from1.6 to 2 min. The run time was 2 min with retention times ofapproximately 0.8 and 1.07 min for Estradiol and Estrone, respectively.Detection was performed on a API 5000 LC/MS/MS system with a triplequadrupole mass spectrometer, a TURBO V ion source, in multiple reactionmonitoring (MRM) mode at positive polarity with APCI probe. The MRMpairs were m/z 273.1 to m/z 107.0 and m/z 271.3 to 107.0. for Estradioland Estrone, respectively. The dwell times were 100 ms for eachtransition and a depolarization and collision energy of 100 and 40,respectively. Data from MS signals was using area under curve (AUC).Ratio=Estrone/(Estrone+Estradiol)

In Vitro 17bHSD13 Cell Assay

Inhibition of 17bHSD13 was measured in a cell-based assay with overexpressed HSD17β13 in HEK293S cells, measuring estradiol to estroneconversion by LCMS/MS.

Cells were plated in 384 well plates (GREINER CELL culture plate 384wblack/clear Poly-D-Lysine) at 10 K c/w in 30 μl of culture media (DMEMwith GLUTAMAX plus 10% FBS). After the cells were allowed to attach for6 h, 0.15 μl of 10 concentration of compounds and 0.03 μl of 10 mMEstradiol (SIGMA, E8875) in DMSO, was added using ECHO dispensing(BECKMAN COULTIER). After 18 h of cell culturing for 20 μl of media wastransferred using BRAVO dispensing robot (AGILENT) to a GREINER PP 384well plate (781280) and 40 μl of 50% acetonitrile was added. Sampleswere analyzed using LC-MS/MS.

SCIEX LC-MS/MS system: Sample was injected with CTC analytical injector,SHIMATZU LC pumps LC20 and analysed on the SCIEX API 5000 LCMSMS systemwith the following settings. Samples were chromatographed on a WATERS,symmetry, C8, 3.5 μm, 2.1×50 mm) column at constant flow rate of 0.5mL/min. The mobile phases consist of A (water with 0.2% formic acid) andB (acetonitrile with 0.2% formic acid). The LC gradient profile is asfollows: 50% B during 0 to 0.5 min, a linear increase to 100% B during0.5 to 1 min, hold at 100% B during 1 to 1.6 min then back to 50% B from1.6 to 2 min. The run time was 2 min with retention times ofapproximately 0.8 and 1.07 min for Estradiol and Estrone, respectively.Detection was performed on a API 5000 LC/MS/MS system with a triplequadrupole mass spectrometer, a TURBO V ion source, in multiple reactionmonitoring (MRM) mode at positive polarity with APCI probe. The MRMpairs were m/z 273.1 to m/z 107.0 and m/z 271.3 to 107.0. for Estradioland Estrone, respectively. The dwell times were 100 ms for eachtransition and a depolarization and collision energy of 100 and 40,respectively. Data from MS signals was using area under curve (AUC).Ratio=Estrone/(Estrone+Estradiol)

In Vitro 17bHSD4 Enzyme Assay

10 concentration of compounds (0.2 μl) in DMSO was added to GREINERFLUOTRAC 200 384 well plate (781076) using ECHO dispensing (BECKMANCOULTER). 80 nl of 10 mM Estradiol (SIGMA, E8875) was added using Echodispensing. The enzyme reaction was initiated by addition, usingMULTIDROP COMBI dispensing (THERMO FISHER), of 40 μl of a mix containingrecombinant 17bHSD4 (M1-N311) and NAD. Final assay conditions were 40 nMof 17bHSD4, 0.125 mM of NAD, 15 μM Estradiol and various concentrationsof compound in buffer (5 mM EDTA (TEKNOVA E0306), 0.01% DDM (AFFYMETRIXD310) in 50 mM Tris-Cl, pH 7.4). After each addition plates werecentrifuged for 1 min at 150×g (EPPENDORF, 5810R, A-4-81). NADHformation was measured by fluorescence intensity (FI) (Ex360/Em460) attime zero (t₀) and at 1.5 h (t₁) in a PHERASTAR FSX (BMG LABTECH). FIfor each sample was calculated as FI at t₁ minus FI at t₀.

In Vitro 17bHSD9 Cell Assay

Inhibition of 17bHSD9 was measured in a cell-based assay with overexpressed HSD17β9 in HEK293S cells, measuring retinol to retinalconversion by LCMS/MS.

Cells were plated in 384 well plates (GREINER CELL culture plate 384wblack/clear Poly-D-Lysine) at 10 K c/w in 30 μl of culture media (DMEMwith GLUTAMAX plus 10% FBS). After the cells were allowed to attach for6 h, 0.15 μl of 10 concentration of compounds and 0.015 μl of 10 mMall-trans-retinol (CAYMAN CHEMICAL, 20241) in DMSO, was added using ECHOdispensing (BECKMAN COULTIER). After 18 h of cell culturing for 20 μl ofmedia was transferred using BRAVO dispensing robot (AGILENT) to aGREINER PP 384 well plate (781280) and 40 μl of 50% acetonitrile wasadded. Samples were analyzed using LC-MS/MS.

SCIEX LC-MS/MS system: Sample was injected with CTC analytical injector,SHIMATZU LC pumps LC20 and analysed on the SCIEX API 5000 LCMSMS systemwith the following settings. Samples were chromatographed on a WATERS,symmetry, C8, 3.5 μm, 2.1×50 mm) column at constant flow rate of 0.5mL/min. The mobile phases consists of A (water with 0.2% formic acid)and B (acetonitrile with 0.2% formic acid). The LC gradient profile isas follows: 50% B during 0 to 0.1 min, a linear increase to 100% Bduring 0.1 to 0.8 min, hold at 100% B during 0.8 to 1.5 min then back to50% B from 1.5 to 1.6 min and hold during run time. The run time was 2min with retention times of approximately 1.54 and 1.62 min for Retinoland Retinal, respectively. Detection was performed on a API 5000LC/MS/MS system with a triple quadrupole mass spectrometer, a TURBO Vion source, in multiple reaction monitoring (MRM) mode at positivepolarity with ESI probe. The MRM pairs were m/z 269.3 to m/z 93.0 andm/z 285.2 to 161.0. for Retinol and Retinal, respectively. The dwelltimes were 100 ms for each transition and a depolarization and collisionenergy of 50 and 25, respectively. Data from MS signals was using areaunder curve (AUC). Ratio=Retinal/(Retinal+Retinol).

Data Analysis

GENEDATA SCREENER was used for curve fitting and calculation of IC₅₀values.

Compound effect was calculated with the formula below;

Compound % effect=−100×((X−min)/(max−min))

where X represents the effect in the presence of test compound, min isDMSO and max is the maximum inhibition of enzyme using a known inhibitoras control.

TABLE 3 17bHSD13 17HSD17b4 17bHSD1713 17bHSD9 Enzyme assay Enzyme assayCell assay Cell assay Example IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) 10.308 32.4 0.75 2 0.075 6.7 1.61 >50 3 0.036 31.5 0.03 >50 4 0.036 6.10.08 13.0 5 0.093 2.61 >50 6 0.041 89.1 0.98 >50 7 0.083 >50 5.05 80.047 6.7 0.61 25.0 9 0.422 >50 5.55 24.9 10 0.474 >50 4.14 >50 110.069 >50 0.80 >50 12 4.335 >50 13 0.040 15.6 0.46 14 0.126 41.40.26 >50 15 0.489 37.7 0.97 16 0.137 15.4 4.56 >50 17 0.525 3.10 180.080 17.8 0.79 6.2 19 0.108 19.6 2.01 20 0.063 9.3 2.40 29.4 21 0.0325.7 0.66 22.6 22 0.532 >50 1.12 >50 23 0.141 33.9 0.93 >50 24 0.198 3.5025 0.288 24.8 0.82 22.7 26 0.278 2.97 27 0.382 4.09 28 0.368 4.13 290.157 17.6 0.44 16.3 30 0.061 17.2 2.52 15.8 31 0.165 11.5 1.06 30.0 320.159 >50 0.30 15.8 33 0.034 8.5 1.21 >50 34 0.581 >50 >50 >50 35 0.64042.2 2.22 4.2 36 1.034 >50 1.32 >50 37 0.057 30.5 0.03 10.0 38 0.20724.0 0.27 8.7 39 1.745 >50 1.48 >50 40 0.700 >50 1.46 >50 41 0.082 >500.09 49.6 42 0.908 >50 10.01 >50 43 0.339 39.0 0.24 18.4 44 0.432 38.40.19 11.2 45 0.466 >50 0.51 4.1 46 0.517 >50 0.37 7.7 47 0.183 47.4 0.232.1 48 0.388 >50 1.10 >50 49 1.669 >50 0.54 >50 50 0.499 >50 0.22 39.551 1.687 >50 2.69 >50 52 0.281 34.6 0.48 1.2 53 2.782 >50 5.61 >50 540.392 >50 0.15 >50 55 0.112 0.96 56 0.142 23.5 1.36 57 0.088 32.30.14 >50 58 0.103 20.6 1.08 59 0.608 3.47 >50 60 0.137 11.0 2.98 610.050 0.73 >50 62 0.046 3.0 0.96 15.8 63 0.151 1.19 64 0.048 5.6 0.2711.2 65 0.134 0.20 66 0.187 19.3 0.25 >50 67 0.079 4.0 0.53 >50 68 0.04426.3 0.80 30.4 69 0.131 48.7 0.11 21.9 70 0.242 2.22 71 0.068 28.36 720.062 19.0 1.12 >50 73 0.088 21.57 >50 74 0.089 21,1 3.00 >50 75 0.2685.60 76 0.128 44.8 0.14 19.6 77 0.075 7.0 0.17 6.8 78 0.127 8.5 0.80 790.106 1.39 80 0.111 21.9 0.46 8.2 81 0.095 0.41 >50 82 0.062 25.90.45 >50 83 0.102 14.4 2.88 84 0.198 19.8 0.30 >50 85 0.317 21.7 3.38 860.102 8.5 0.54 21.1 87 0.285 >200 0.06 36.3 88 0.468 36.4 0.19 41.7 890.168 >50 0.07 >50 90 0.626 >50 1.69 91 0.166 >50 92 0.041 >50 1.54 >5093 0.063 22.2 0.70 40.3 94 0.048 23.6 1.42 >50 95 0.053 6.9 0.21 17.0 960.047 18.0 0.17 17.3 97 0.122 26.2 0.89 98 0.063 9.5 0.52 40.2 99 0.11441.8 15.82 38.9 100 5.338 18.13 101 0.050 >50 0.42 >50 102 0.052 >500.70 >50 103 0.026 6.5 0.53 24.9 104 0.057 9.6 0.54 105 3.759 1.26 1060.516 8.2 1.22 >50 107 0.143 10.5 0.37 5.0 108 0.080 >50 0.49 >50 1090.046 11.7 1.70 >50 110 1.009 >50 0.24 >50 111 0.093 >50 0.10 >50 1120.197 >50 0.39 32.4 113 0.211 45.3 0.10 >50 114 0.046 >50 0.12 15.8 1150.154 >50 0.10 32.5 116 0.117 >50 0.06 >50 117 0.234 39.9 0.09 >50 1181.080 >50 0.22 >50 119 1.735 >50 2.75 >50 120 0.044 >50 0.14 >50 1210.130 >50 0.02 16.4 122 0.085 >50 0.04 8.3 123 0.077 32.0 0.08 30.0 1240.042 24.1

The data in Table 3 may be from a single experiment or an average of twoor more experiments.

Assay A: Metabolic Stability in Human Hepatocytes

Hepatocyte metabolic stability was determined in accordance with themethod described by Jacobson et al., An optimized automated assay fordetermination of metabolic stability using hepatocytes: assayvalidation, variance component analysis, and in vivo relevance. AssayDrug Dev Technol 2007, 5 (3), 403-415. DOI: 10.1089/adt.2007.059, whichis incorporated herein by reference. Cryopreserved hepatocytes at aconcentration of 10⁶ viable cells/mi were used. After thawing,hepatocytes were incubated for 10 min to warm to 37° C. and testcompounds, dissolved in acetonitrile, were added to give a finalconcentration of 1 μM. At 0.5, 5, 15, 30, 45, 60, 80, 100 and 120 min,the incubation system was mixed and 20 μL aliquots were transferred ateach time point to wells in a separate plate filled with 80 &L MeCN tostop the reaction. The quenching plate was then vortexed followed bycentrifugation, and supernatants were analyzed by LC-MS/MS. Peak areaswere determined from extracted ion chromatograms, and the in vitrointrinsic clearance (in vitro CLint, in μL/min/10⁶ cells) of parentcompound was calculated from the slope in the regression analysis of thenatural logarithm of parent concentration vs time curve.

Assay B: Cytochrome P450 Inhibition 2C9

A fluorescence-based method in 96-well format was used to determine theinhibition of 2C9 (Crespi, C. L. et al., Microtiter plate assays forinhibition of human, drug-metabolizing cytochromes P450. AnalBiochem1997, 248 (1), 188-190. DOI: 10.1006/abio.1997.2145, which isincorporated herein by reference). The recombinant human enzymes usedwere prepared in house, except for CYP2D6 (CYPEX LTD, Dundee, UK).Different coumarin substrates, biotransformed into fluorescentmetabolites, were used as probes for each individual CYP. A fluorescenceplate reader (SPECTRAMAX GEMINIXS, MOLECULAR DEVICES, Sunnyvale,California, USA) was used to measure the levels of metabolites formed. Adilution series of the test substrates was prepared at eight differentconcentrations. For each CYP, a mixture of the enzyme, correspondingcoumarin substrate, potassium phosphate buffer pH 7.4 and water(concentrations and volumes were CYP-dependent) were added to each wellin a black 96-well plate. The test substrates at differentconcentrations were added. After 10 min pre-incubation, the co-factorNADPH was added to initiate the reaction. After 20-50 min (CYP andsubstrate-dependent) the reaction was terminated by addition oftrisbase/MeCN (20:80). The plates were transferred to the fluorescenceplate reader where the wavelengths were set individually for thedifferent coumarin substrates and their respective fluorescentmetabolite. The responses were exported to Excel where the IC₅₀ curveswere plotted (percent inhibition versus concentration) and IC₅₀ valuescalculated for each test substrate and enzyme using XL-fit.

Assay C: CB1 Agonism Assay

Evaluation of the agonist activity of compounds at the human CB1receptor expressed in transfected CHO cells, determined by measuringtheir effects on cAMP modulation using the HTRF detection method.

Experimental protocol: The cells are suspended in HBSS buffer(INVITROGEN) complemented with 20 mM HEPES (pH 7.4), then distributed inmicroplates at a density of 5·103 cells/well in the presence of eitherof the following: HBSS (basal control), the reference agonist at 30 nM(stimulated control) or various concentrations (EC₅₀ determination), orthe test compounds. Thereafter, the adenylyl cyclase activator NKH 477is added at a final concentration of 3 μM. Following 20 min incubationat 37° C., the cells are lysed and the fluorescence acceptor (D2-labeledcAMP) and fluorescence donor (anti-cAMP antibody labeled with europiumcryptate) are added. After 60 min at room temperature, the fluorescencetransfer is measured at gex=337 nm and gem=620 and 665 nm using amicroplate reader (RUBYSTAR, BMG). The cAMP concentration is determinedby dividing the signal measured at 665 nm by that measured at 620 nm(ratio). The results are expressed as a percent of the control responseto 30 nM CP 55940. The standard reference agonist is CP 55940, which istested in each experiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

Bibliographic reference Felder, C. C. et al., (1995), Comparison of thepharmacology and signal transduction of the human cannabinoid CB1 andCB2 receptors, Mol. Pharmacol., 48: 443, which is incorporated herein byreference.

TABLE 4 Assay A: Human Heps Met Assay B: CYP2C9 HLM Assay C: CB1 Hu CHOCAMP Clint GMean CLint Diclofenac LC/MSMS TRF Ag CR Example (μl/min/1E6)GMean IC₅₀ (μM) GMean EC₅₀ (μM) 2 14.7 1.8 3 1.6 >100 4 47.4 0.6 1.9 53.0 7 8.4 9 262.2 5.7 11 >300 12.8 3.1 12 21.2 14 14.3 1.1 15 59.8 2.116 56.8 0.8 17 6.5 0.2 18 17.2 0.4 19 4.3 1.0 20 16.8 0.4 21 13.3 0.2 226.3 1.2 26 9.2 4.4 27 14.0 3.1 29 16.9 0.2 30 15.6 3.9 31 12.6 5.0 324.1 8.3 33 124.3 0.2 37 6.7 7.8 2.5 38 2.1 14.8 41 5.9 15.4 43 3.3 13.947 17.4 1.0 50 4.3 17.2 56 5.9 5.1 57 9.5 3.7 58 24.6 7.3 59 10.2 13.160 13.8 3.9 66 12.1 3.1 3.2 67 6.6 3.0 69 13.1 2.4 70 12.4 18.4 74 14.41.8 76 18.2 2.6 77 13.4 0.3 78 28.2 3.0 79 10.1 2.0 80 9.8 3.3 82 15.44.3 83 11.8 6.2 85 14.1 3.4 9.3 86 12.3 4.0 5.7 87 2.7 15.4 46.0 88 3.616.8 89 14.6 3.7 78.2 90 >300 >30 93 15.6 1.3 94 17.3 1.2 95 12.9 1.1 961.3 97 46.6 1.8 98 26.7 0.8 99 >300 >30 103 0.8 106 16.1 5.9 108 8.8 7.0109 13.0 14.8 111 4.9 3.4 112 7.4 5.4 113 7.3 4.2 0.4 114 6.4 7.2 60.5115 6.2 9.8 >100 117 4.2 4.9 0.5 118 4.6 7.8 119 1.0 12.3 120 13.3 12.88.5 121 6.8 7.7 >10 122 8.8 4.4 22.3 123 8.3 9.3 >3.0 124 11.1 27.0

The data in Table 4 may be from a single experiment or an average of twoor more experiments.

Metabolism Study

An in vitro study to identify metabolites of Example 87 yieldedMetabolite 1 and Metabolite 2, as defined below. Metabolites 1 and 2were subsequently synthesised and characterised.

Metabolite 1:3-(3-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-1,2,4-oxadiazol-5-yl)-2,5,6-trifluorophenylhydrogen sulfate

A solution of((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone,Example 87, (60 mg, 0.17 mmol) and TEA (38 μL, 0.27 mmol) in anhydrousDCM (2.76 ml) was treated with pyridine-sulfur trioxide (1/1) (160 mg,1.01 mmol) and the reaction mixture was stirred at rt for 5 min. Thesolid formed was removed by filtration, water was added to the filtrate,and the aqueous phase was washed with DCM. The pH of the aqueous phasewas adjusted to 7-8 using NaHCO₃. Freeze drying gave the sodium salt ofthe desired product (23 mg, 30%); HRMS (ESI) m/z [M+H]⁺ calcd forC₁₅H₁₄F₃N₃O₇S: 436.0426, found: 436.0429.

Metabolite 2:(2S,3S,4S,5R,6S)-6-(3-(3-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-1,2,4-oxadiazol-5-yl)-2,5,6-trifluorophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylicAcid

Ag₂O (2.5 eq) was added to a solution of((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone,Example 87, (1 eq), and(2R,3R,4S,5S,6S)-2-bromo-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (0.9 eq) in MeCN (0.1 M) in a reaction vessel covered withaluminum foil, and the reaction mixture was stirred at room temperatureovernight The reaction mixture was filtered through CELITE and thefiltrate was diluted with EtOAc and then concentrated at reducedpressure. The crude compound was purified by preparative HPLC on aXBRIDGE C18 column (10 μm, 250×19 mm ID) using a gradient of MeCN inH₂O/MeCN/NH₃ (95/5/0.2) as mobile phase. The acetate groups and theester were hydrolyzed in MeCN (0.07 M) by treatment with TEA (12 eq) andLiBr (40 eq) at rt for 4 h. Water was added to the reaction mixture andthe mixture was acidified using HCl. The mixture was concentrated atreduced pressure and the crude compound was purified by preparativeHPLC, PrepMethod D (gradient: 0-100%) to give the title compound; HRMS(ESI) m/z [M−H]⁻ calcd for C₂₁H₂₁F₃N₃O₁₀: 532.1179, found: 532.1195.

The above description of illustrative embodiments is intended only toacquaint others skilled in the art with the Applicant's specification,its principles, and its practical application so that others skilled inthe art may readily adapt and apply the specification in its numerousforms, as they may be best suited to the requirements of a particularuse. This description and its specific examples, while indicatingembodiments of this specification, are intended for purposes ofillustration only. This specification, therefore, is not limited to theillustrative embodiments described in this specification, and may bevariously modified. In addition, it is to be appreciated that variousfeatures of the specification that are, for clarity reasons, describedin the context of separate embodiments, also may be combined to form asingle embodiment. Conversely, various features of the specificationthat are, for brevity reasons, described in the context of a singleembodiment, also may be combined to form sub-combinations thereof.

1. A compound of Formula (I);

wherein, A is selected from

each R^(A) is independently selected from H, halo, R^(X), —OR^(x), and—CN, wherein each R^(X) is independently C₁₋₃ alkyl optionallysubstituted with one to three F; R^(B) is halo, —CHF₂, —CF₃, —OCHF₂ or—OCF₃; one of X¹, X² and X³ is selected from NH, O and S and the othertwo of X¹, X² and X³ are independently selected from N and CR^(Y),wherein each R^(Y) is independently H, —CN, —C(═O)N(R⁷)₂ or R^(XA),wherein R^(XA) is independently C₁₋₃ alkyl optionally substituted withone to three F; R¹ and R² are such that; (i) R¹ and R², taken togetherwith the N atom to which they are attached, form a ring system, whereinthe ring system is optionally substituted with one or more R^(C),wherein each R^(C) is independently selected from F, R³, R⁴, —O(R⁴),—O(R⁵), R³, R⁶, —OH, —CN, oxo and —C(═O)N(R^(7A))₂; (ii) R¹ is selectedfrom R⁸ and R^(4A), and R² is selected from R^(8A) and H; or (iii) R¹ isR^(5A) and R² is R^(8B); each R³ is independently C₁₋₄ alkyl or C₃₋₆cycloalkyl, each of which are optionally substituted with one or moregroups independently selected from R^(4X), R^(5x), —O(R^(4X)),—O(R^(5X)) and F; each R^(3X) is independently C₁₋₄ alkyl or C₃₋₆cycloalkyl, each of which are optionally substituted with one or more F;each R⁴ and R^(4B) are independently monocyclic or bicyclic 5 to 9membered heteroaryl, each of which are optionally substituted with oneor more groups independently selected from R^(4X), —O(R^(4X)), R^(5X),—O(R^(5X)), —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH, —C(═O)O(C₁₋₄ alkyl),—C(═O)N(R^(7B))₂, R³ and halo; R^(4A) is a 5 membered monocyclicheteroaryl, optionally substituted with one or more groups independentlyselected from R^(4X), —O(R^(4X)), R^(5X), —O(R^(5X)), —OH, —CN, C₁₋₄alkoxy, —C(═O)OH, —C(═O)O(C₁₋₄ alkyl), —C(═O)N(R^(7B))₂, R³ and halo;each R⁵, R^(5A) and R^(5B) are independently phenyl, each of which areoptionally substituted with one or more groups independently selectedfrom R^(4X), —O(R^(4X)), R^(5X), —O(R^(5X)), —OH, —CN, C₁₋₄ alkoxy,—C(═O)OH, —C(═O)O(C₁₋₄ alkyl), —C(═O)N(R^(7B))₂, R³ and halo; eachR^(4X) is independently monocyclic or bicyclic 5 to 9 memberedheteroaryl, each of which are optionally substituted with one or moregroups independently selected from —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH,—C(═O)N(R^(7B))₂, R^(3X) and halo; each R^(5X) is independently phenyl,each of which are optionally substituted with one or more groupsindependently selected from —OH, —CN, C₁₋₄ alkoxy, —C(═O)OH,—C(═O)N(R^(7B))₂, R^(3x), and halo; R⁶ is C₁₋₄ alkoxy optionallysubstituted with one or more groups independently selected from R^(4X),R^(5x) and F; each R⁷, R^(7A), R^(7B) and R^(7C) are independently H,C₁₋₄ alkyl or C₃₋₆ cycloalkyl; R⁸, R^(8A), R^(8B) are independently C₁₋₄alkyl or C₃₋₆ cycloalkyl, each of which are optionally substituted withone or more groups independently selected from R^(4B), R^(5B), F, —OH,—CN, C₁₋₄ alkoxy, —C(═O)O(C₁₋₄ alkyl) and —C(═O)N(R^(7C))₂; wherein thering system is a saturated or partly saturated, monocyclic, bicyclic ortricyclic, 4-13 membered ring comprising one N atom, and optionally oneor two further heteroatoms independently selected from N, O and S; andwherein each heteroaryl is independently an aromatic ring containing oneor more heteroatoms independently selected from N, O and S, or apharmaceutically acceptable salt thereof.
 2. A compound of Formula (I)or a pharmaceutically acceptable salt thereof, as claimed in claim 1,wherein (i) X¹ is N, X² is O and X3 is N; (ii) X¹ is N, X² is N and X3is O; (iii) X¹ is CR^(Y), X² is CR^(Y) and X³ is S; (iv) X¹ is O, X² isN and X³ is CR^(Y); (v) X¹ is N, X² is O and X³ is CR^(Y); (vi) X¹ isCR^(Y), X² is N and X³ is O; (vii) X¹ is O, X2 is N and X3 is N; (viii)X¹ is N, X² is N and X3 is S; (ix) X¹ is CR^(Y), X² is S and X³ isCR^(Y); or (x) X¹ is CR^(Y), X² is N and X3 is S.
 3. A compound ofFormula (I) or a pharmaceutically acceptable salt thereof, as claimed inclaim 1, wherein one of X¹, X² and X³ is O and the other two of X¹, X²and X³ are independently selected from N and CR^(Y).
 4. A compound ofFormula (I) or a pharmaceutically acceptable salt thereof, as claimed inclaim 1, wherein X¹ is N, X² is O and X³ is N.
 5. A compound of Formula(I) or a pharmaceutically acceptable salt thereof, as claimed in claim1, wherein one of X¹, X² and X³ is S and the other two of X¹, X² and X³are independently CR^(Y).
 6. A compound of Formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim 1, whereineach R^(A) is independently H or halo.
 7. A compound of Formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim 1, whereineach R^(A) is independently H or F.
 8. A compound of Formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim 1, whereinA is


9. A compound of Formula (I) or a pharmaceutically acceptable saltthereof, as claimed in claim 1, wherein R^(B) is F.
 10. A compound ofFormula (I) or a pharmaceutically acceptable salt thereof, as claimed inclaim 1, wherein R¹ and R², taken together with the N atom to which theyare attached, form a ring system, wherein the ring system is optionallysubstituted with one or more R^(C).
 11. A compound of Formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim 1, whereinthe ring system is an aliphatic, monocyclic or bicyclic, 4-11 memberedring comprising one N atom, and optionally one further heteroatomselected from N, O and S.
 12. A compound of Formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim 1, whereinR¹ and R², taken together with the N atom to which they are attachedform a ring system selected from a 4-8 membered monocyclicheterocycloalkyl, an 8-11 membered spirocyclic bicyclic heterocycloalkyland a 7-10 membered fused bicyclic heterocycloalkyl, wherein the ringsystem is optionally substituted with one or more R^(C), and whereinheterocycloalkyl is a saturated ring comprising one N atom, andoptionally one further heteroatom selected from N, O and S.
 13. Acompound of Formula (I) or a pharmaceutically acceptable salt thereof,as claimed in claim 1, wherein R¹ and R², taken together with the N atomto which they are attached form a ring system that is a 4-8 memberedmonocyclic heterocycloalkyl optionally substituted with one or moreR^(C), wherein heterocycloalkyl is a saturated ring comprising one Natom, and optionally one further heteroatom selected from N, O and S.14. A compound of Formula (I) or a pharmaceutically acceptable saltthereof, as claimed in claim 1, wherein R¹ and R², taken together withthe N atom to which they are attached form a ring system that is a 5-7membered monocyclic heterocycloalkyl optionally substituted with one ormore R^(C), wherein heterocycloalkyl is a saturated ring comprising oneN atom, and one further heteroatom selected from N, O and S.
 15. Acompound of Formula (I) or a pharmaceutically acceptable salt thereof,as claimed in claim 1, wherein the ring system is optionally substitutedwith one to three groups independently selected from R³, R⁴ and R⁵. 16.A compound of Formula (I), or a pharmaceutically acceptable saltthereof, as claimed in claim 1, that is a compound of Formula (II):

wherein J is selected from O, S, CH₂, NH and a covalent bond, G iseither absent or, together with the carbon atoms to which it isattached, forms a C₃₋₆ cycloalkane ring; Z is such that (i) where G isabsent and J is selected from O, S, CH₂ and a covalent bond, Z isselected from CH₂, CH₂CH₂ and C₃₋₆ cycloalkylidyne, (ii) where G isabsent and J is NH, Z is selected from CH₂, CH₂CH₂, C₃₋₆ cycloalkylidyneand C(═O), and (iii) where G, together with the carbon atoms to which itis attached, forms a C₃₋₆ cycloalkane ring, Z is CH₂; x is selected from0 to 3; and each R⁹ is independently selected from R³, R⁴ and R⁵, or apharmaceutically acceptable salt thereof.
 17. A compound of Formula (I),or a pharmaceutically acceptable salt thereof, as claimed in claim 1,that is a compound of Formula (III):

wherein J is selected from O, S, CH₂, NH and a covalent bond, x isselected from 0 to 3; each R⁹ is independently selected from R³, R⁴ andR⁵; and R^(E) is H or halo, or a pharmaceutically acceptable saltthereof.
 18. A compound of Formula (I), or a pharmaceutically acceptablesalt thereof, as claimed in claim 16, wherein J is O. 19-24. (canceled)25. A compound of Formula (I) or a pharmaceutically acceptable saltthereof, as claimed in claim 1, wherein each R³ is independently C₁₋₄alkyl optionally substituted with one to three F.
 26. A compound ofFormula (I) or a pharmaceutically acceptable salt thereof, as claimed inclaim 1, wherein each R⁴ and R^(4B) are independently monocyclic orbicyclic 5 to 9 membered heteroaryl, each of which are optionallysubstituted with one or more groups independently selected from OH, —CN,C₁₋₄ alkoxy, —C(═O)OH, —C(═O)O(C₁₋₄ alkyl) —C(═O)N(R^(7B))₂, R^(3X) andhalo.
 27. A compound of Formula (I) or a pharmaceutically acceptablesalt thereof, as claimed in claim 1, wherein each R⁵, R^(5A) and R^(5B)are independently phenyl, each of which are optionally substituted withone or more groups independently selected from OH, —CN, C₁₋₄ alkoxy,—C(═O)OH, —C(═O)O(C₁₋₄ alkyl), —C(═O)N(R^(7B))₂, R^(3X) and halo.
 28. Apharmaceutical composition comprising a compound of Formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim 1, and apharmaceutically acceptable excipient. 29.-32. (canceled)
 33. A methodof treating liver disease in a patient comprising administering to thepatient a compound of Formula (I) or a pharmaceutically acceptable saltthereof, as claimed in claim 1.